CN101232885A - Substituted pyridazinyl- and pyrimidinyl-quinolin-4-ylamine analogues - Google Patents
Substituted pyridazinyl- and pyrimidinyl-quinolin-4-ylamine analogues Download PDFInfo
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- CN101232885A CN101232885A CNA2006800031817A CN200680003181A CN101232885A CN 101232885 A CN101232885 A CN 101232885A CN A2006800031817 A CNA2006800031817 A CN A2006800031817A CN 200680003181 A CN200680003181 A CN 200680003181A CN 101232885 A CN101232885 A CN 101232885A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Substituted pyridazinyl- and pyrimidinyl-quinolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.
Description
Technical field
The present invention is roughly about what have that medicine is suitable for character and is substituted pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog.The present invention further about use these chemical compounds in the purposes of the treatment patient's condition relevant with the capsaicin receptor activation, be used to identify the purposes of other and the bonded medicament of capsaicin receptor, and be used for purposes as capsaicin receptor detection and localized probe.
Prior art
Pain perception, or injury sensation are that all edge tails that are subjected to a group to be called the specialization sensory neuron of " nociceptor (nociceptor) " are regulated.There are multiple physics and chemical stimulation meeting to bring out these neuronic activation, cause the identification of possibility destructive stimulus mammal.Yet nociceptor activation improper or excessive can cause the acute or chronic pain that makes the people suffer all kinds of tormenting.
Neuropathic pain relates to the transmission of the pain signal when not stimulating, typically by due to the nervous system injury.In most cases, these pain are considered to cause periphery with due to central nervous system's sensitization because of perimeter systems is subjected to first injury back (for example: via direct injury or systemic disease).Scorching hot, sharp-pointed pain that neuropathic pain is typically, and its intensity not only can not slow down sometimes also may be along with the deterioration of the first injury of bringing out this pain or disease shape mill people more.
Existing facture to neuropathic pain is invalid mostly.Opium (as: morphine) is the analgesic of brute force, but owing to its adverse side effect makes its suitability limited, as: physiological addiction and give up characteristic, and the enterokinesia of respiration inhibition, emotion changes and concurrent constipation descends, feels sick, vomiting, and endocrine and autonomic nervous system change.In addition, neuropathic pain does not often react or only has partly traditional class Opium analgesic therapy and reacts.Using N-methyl D-Radix Asparagi amino acid antagonist to restrain his life (ketamine) or α (2)-epinephrine swashs the property led agonist clonidine (clonidine) and can alleviate acute or chronic pain, and can reduce the consumption of class opiate, but these preparations often can't tolerate because of side effect.
Past attempts is used the chronic and acute pain of capsaicin topical therapeutic, comprises neuropathic pain.As if capsaicin is a kind of pungent substance derived from Solanaceae (Solanaceae) plant (comprising Fructus Capsici), but optionally act on the afferent nerve fiber (A-δ and C fiber) of the minor diameter of salty letter mediated pain.Response feature to capsaicin is a continuous activation nociceptor in perienchyma, thereby makes peripheral nociceptor reach sensitivity at last to one or more stimulations.By zooscopy as seen, as if capsaicin activates the depolarization of C fibrous membrane by the cation selective channel of opening calcium and sodium.
The capsaicin analog that has class cephrol (vanilloid) part group equally also can cause similar reaction.Wherein a kind of analog be resin toxin (resiniferatoxin) (RTX), be the natural product of Euphorbiaceae (Euphorbia) plant.Class cephrol receptor (VR) is the neuron film identifying position that is used to illustrate capsaicin and these related stimulus chemical compounds.The capsaicin reaction is subjected to the competitive inhibition (and then picking anti-) of another kind of capsaicin analog (capsaicin receptor blocker (capsazepine)), suppressed by non-selective cation channel blocker ammoniated ruthenium oxychloride, these antagonisies combine with VR and are no more than medium affinity (typical Ki value is not less than 140 μ M).
Existing people grows class cephrol receptor from rat and the mankind's dorsal root ganglion cell (dorsal root ganglioncells) choosing.The first kind cephrol receptor that is determined is called 1 type class cephrol receptor (VR1), and term " VR1 " and " capsaicin receptor " commutative in this article use mean this kind of rat and human receptor to reach the mammal congener.The role of VR1 in the pain impression adopted the white mice that lacks this receptor to confirm that this kind white mice can not brought out the pain behavior by the class cephrol, and in damaged condition with the reaction of inflammation to heat.VR1 is a kind of non-selective cation channel, and when being subjected to high temperature, low pH and capsaicin receptor agonists, its open threshold value promptly descends.After this capsaicin receptor channel is open, promptly disengage the inflammatory peptide in the neuron usually, increase pain reaction from the neuron that shows this receptor and near other.After being subjected to the first activation of capsaicin, capsaicin receptor promptly via the phosphorylation reaction of the protein kinase that relies on cAMP, react rapidly by desensibilization.
Because it has the ability of going sensitization of pair nociceptor in perienchyma, so VR1 agonist class cephrol chemical compound has been used as local anesthetic.Yet throwing is given agonist itself and may be caused scorching hot pain, and limits its therapeutic use.Recently existing report points out that VR1 antagonist (comprising some non-class cephrol chemical compound) also is applicable to treatment pain (referring to for example: PCT international application case bulletin case WO 02/08221, WO 03/062209, WO 04/054582, WO04/055003, WO 04/055004, WO 04/056774, WO 05/007646, WO 05/07648, WO 05/007652, WO 05/009977, WO 05/009980, and WO 05/009982).
Therefore, need meeting and VR1 reciprocal action, but can not bring out the chronic and acute pain of compounds for treating of phase pain perception at the beginning of the VR1 agonist class cephrol chemical compound, comprise neuropathic pain, and other symptom that capsaicin receptor regulating action is responded.The present invention can meet this demand, and further advantage is provided.
Summary of the invention
What the invention provides a kind of following facial I is substituted pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog or its pharmaceutically acceptable salt:
Its Chinese style I:
(1) A is that N and B are CR
8, or (2) A is CR
5And B is N;
Y and Z are N or CR independently of one another
1
Each R
1Be hydrogen, halogen, cyano group, amino, C independently
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl, C
1-C
4Halogenated alkoxy or list-or two-(C
1-C
4Alkyl) amino;
R
2For:
(i) hydrogen or halogen; Or
(ii) C
1-C
6Alkyl, (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, C
1-C
6Alkoxyl, C
1-C
6Aminoalkyl, C
1-C
6Hydroxy alkyl, C
2-C
6Alkyl ether, list-or two-(C
1-C
6Alkyl) amino C
0-C
4Alkyl or (4 to 7 element heterocycle alkyl) C
0-C
4Alkyl; Respectively hang oneself 0 to 4 substituent group of above group replaces, and described substituent group is independently selected from halogen, cyano group, hydroxyl, amino, ketone group, list-or two-(C
1-C
6Alkyl) amino, C
1-C
6Alkyl C
1-C
6Alkoxyl or C
1-C
6Haloalkyl; R
3Be hydrogen, COOH, C
1-C
4Alkyl, C
1-C
4Alkoxyl, C
1-C
4Alkoxy carbonyl or and R
2Form the condensed optional ring that is substituted together;
R
4Be hydrogen, halogen, cyano group, amino, COOH, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl, C
1-C
4Halogenated alkoxy or list-or two-(C
1-C
4Alkyl) amino;
Each R
5Be hydrogen, halogen, cyano group, amino, COOH, C independently
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl, C
1-C
4Halogenated alkoxy or list-or two-(C
1-C
4Alkyl) amino;
R
8For:
(i) hydrogen, hydroxyl, halogen, cyano group, amino, amino carbonyl or COOH; Or
(ii) general formula is LR
aGroup;
Ar is 6 to 10 Yuans aryl or 5 to 10 Yuans heteroaryls, and it is respectively hung oneself 0 to 6 and independently is selected from following substituent group and replaces:
(i) ketone group;
(ii) general formula is LR
aGroup; Or
(iii) form the group through 0 to 35 to 7 Yuans annelated heterocycles that substituent group replaced together, described substituent group is independently selected from hydroxyl, halogen, amino, amino carbonyl, cyano group, nitro, ketone group, COOH, C
1-C
8Alkyl, C
1-C
8Alkoxyl, C
1-C
8Alkylthio group, C
1-C
8Alkanoyl, C
1-C
8Alkanoyl oxygen base, C
1-C
8Alkoxy carbonyl, C
1-C
8Alkyl ether, C
1-C
8Hydroxy alkyl, C
1-C
8Haloalkyl, phenyl C
0-C
8Alkyl, list or two (C
1-C
6Alkyl) amino C
0-C
4Alkyl, C
1-C
8Alkyl sulphonyl or (4 to 7 element heterocycle) C
0-C
8Alkyl;
L is independently selected from single covalent bond, O, (C=O), O (C=O), C (=O) O, OC (=O) O, S (O) at every turn when occurring
m, N (R
x), (C=O) N (R
x), N (R
x) (C=O), N (R
x) S (O)
m, S (O)
mN (R
x) or N[S (O)
mR
w] S (O)
mWherein m is independently selected from 0,1 or 2 at every turn when occurring; R
xWhen occurring, be independently selected from hydrogen, C at every turn
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
1-C
6Alkanoyl or C
1-C
6Alkyl sulphonyl; And R
wBe hydrogen or C
1-C
6Alkyl;
R
aWhen occurring, be selected from independently of one another at every turn:
(i) hydrogen, halogen, cyano group or nitro; Or
(ii) C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, C
1-C
8Haloalkyl, C
2-C
8Alkyl ether, list-or two-(C
1-C
8Alkyl) amino or (3 to 10 element heterocycle) C
0-C
6Alkyl; Above group is respectively hung oneself 0 to 6 and independently is selected from following substituent group and replaces:
(a) hydroxyl, halogen, amino, amino carbonyl, cyano group, nitro, ketone group, COOH; Or
(b) C
1-C
8Alkyl, C
2-C
8Thiazolinyl, (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, C
1-C
8Alkoxyl, C
1-C
8Alkylthio group, C
1-C
8Alkanoyl, C
1-C
8Alkanoyl oxygen base, C
1-C
8Alkoxy carbonyl, C
1-C
8Alkyl ether, C
1-C
8Hydroxy alkyl, C
1-C
8Haloalkyl, phenyl C
0-C
8Alkyl, list-or two-(C
1-C
6Alkyl) amino carbonyl, list-or two-(C
1-C
6Alkyl) amino C
0-C
4Alkyl, C
1-C
8Alkyl sulphonyl or (4 to 7 element heterocycle) C
0-C
8Alkyl, above group are respectively hung oneself 0 to 4 and independently are selected from hydroxyl, amino, C
1-C
4Alkyl or C
1-C
4The substituent group of alkoxyl replaces.
In certain aspects, the chemical compound of formula I is the VR1 regulator, and its K in capsaicin receptor affinity analysis test
iBe no more than 1 little not ear (micromolar) concentration, 500 Nai Moer (nanomolar) concentration, 100 Nai Moer concentration, 50 Nai Moer concentration, 10 Nai Moer concentration or 1 Nai Moer concentration and/or the EC in measuring capsaicin receptor agonists or antagonist activities analytical test
50Or IC
50Value is no more than 1 little not ear concentration, 500 Nai Moer concentration, 100 Nai Moer concentration, 50 Nai Moer concentration, 10 Nai Moer concentration or 1 Nai Moer concentration.In some specific embodiment, these VR1 regulators are the VR1 antagonist, and in the capsaicin receptor activation in vitro in the analytical test (as the analytical test that is provided at this paper embodiment 6) equaling IC
50Value, 10 times to IC
50The value or 100 times to IC
50The value concentration the time, do not have the agonist activity that can detect.
In certain aspects, this paper provide chemical compound be with detectable label labelling (for example :) through radioactive label or through the luciferin conjugation.
The present invention further provides medical composition, in others, its comprise at least a formula I chemical compound (as, the chemical compound that this paper provided or its pharmaceutically acceptable salt) with physiology on supporting agent or the excipient composition that can accept.
In aspect another, the invention provides a kind of method that reduces the calcium conduction of cell capsaicin receptor, it by the cell that shows capsaicin receptor (for example: nerve) contact to treat effective concentration with at least a VR1 regulator of this paper explanation comprises.These contacts can be in vivo or in vitro carrying out.
Further provide and suppress the method that class cephrol ligand combines with capsaicin receptor.In some these aspect, inhibitory action lies in vitro carries out.These methods comprise at least a VR1 regulator that this paper is illustrated, suppress to contact with capsaicin receptor under the condition and consumption or concentration that class cephrol ligand combines with capsaicin receptor in being enough to detect.In other these aspects, capsaicin receptor ties up in patient's body.These methods comprise the illustrated VR1 regulator of at least a this paper of cells contacting that makes performance capsaicin receptor in patient's body, the used concentration of its VR1 suppresses the combination that class cephrol ligand is grown the capsaicin receptor cell to performance through choosing for being enough to detect in vitro testing, therefore suppress the combination of class cephrol ligand to the capsaicin receptor in patient's body.
The present invention still provides the method for the symptom that in a kind of treatment patient body the capsaicin receptor regulating action is responded, and it comprises throws the illustrated VR1 regulator of at least a this paper that gives medical effective dose to the patient.
In others, a kind of method of patient treatment pain that is is provided, it comprises that the patient to suffering from (or risky suffering from) pain throws the bright VR1 regulator of at least a this paper institute's saying that gives medical effective dose.
Still propose the method for the scratching where it itches of a kind of treatment patient, urinary incontinence, overactive bladder, cough and/or singultus, it comprises throws the illustrated VR1 regulator of at least a this paper with medical effective dose to the patient who suffers from (or risky suffering from) above-mentioned one or more symptoms.
The method that the present invention still provides a kind of promotion obese patient to lose weight, it comprises at least a this paper illustrated VR1 regulator of obese patient's throwing with medical effective dose.
The method provides again as the evaluation that combines medicament with capsaicin receptor, it comprises: (a) with capsaicin receptor and the illustrated underlined VR1 regulator of this paper, under the condition that can make VR1 regulator and capsaicin receptor combination, contact, use generation in conjunction with it underlined VR1 regulator; (b) there is detection down and combines the corresponding signal of it underlined VR1 regulator content in no test preparation; (c) will contact with test preparation in conjunction with it underlined VR1 regulator; (d) in the presence of test preparation, detect and combine the corresponding signal of it underlined VR1 regulator content; And the signal that (e) is detected with step (b) relatively, the signal of determination step (d) reduction degree.
In aspect another, the invention provides the method that whether contains capsaicin receptor in a kind of decision sample, it comprises: (a) sample and the illustrated VR1 regulator of this paper are contacted under the condition that can make chemical compound and capsaicin receptor combination; Detect the VR1 that combines with capsaicin receptor with (b) and regulate dosage.
The present invention also provides a kind of pharmaceutical preparation of packing, and it comprises: (a) be contained in the illustrated medical composition of this paper in the container; Use the description of one or more symptoms that the said composition treatment responds to the capsaicin receptor regulating action with (b), as: pain, scratch where it itches, urinary incontinence, overactive bladder, cough, singultus and/or obesity.
In aspect another again, the invention provides the method for a kind of preparation chemical compound disclosed herein (comprising intermedium).
The present invention these and others can be understood with reference to following detailed description.
Embodiment
As above-mentioned, the invention provides be substituted have a useful medicinal properties be substituted pyridazinyl-quinolyl-4 amine and pyrimidine radicals-quinolyl-4 amine analog.These chemical compounds can be used in vitro or in vivo, regulate (best for suppressing) capsaicin receptor activity according to multiple mode.
The term explanation
Usually adopt standardized denomination explanation chemical compound herein.Chemical compound (except as otherwise noted, otherwise) with asymmetric center comprises all optical isomeric compounds and its mixture.In addition, Z-and E-type may appear in the chemical compound with carbon-to-carbon double bond, and all heterogeneous of chemical compound include in the present invention except as otherwise noted.If when chemical compound was multiple tautomerism type, the chemical compound that is shown was not limited to any specific compounds tautomeric, and hope comprises all tautomerism types.Some series of compounds (for example: R illustrates with the general formula that comprises code name herein
1, A
1, X).Except as otherwise noted, otherwise the definition of each code name is independent with other code name respectively in these chemical formulas, and the definition when the once above code name of any appearance occurs at every turn in the chemical formula is also independent respectively.
Term " is substituted pyridazinyl-quinolyl-4 amine and pyrimidine radicals-quinolyl-4 amine analog " and is used for all formula I chemical compounds of this paper middle finger, and the pharmaceutically acceptable salt of these chemical compounds.These chemical compounds comprise that wherein quinoline core is the analog of modifying by adding theheterocyclic nitrogen atom, and on core texture the analog of attached various substituent groups (as described in below).In other words, the chemical compound of quinolyl-4 amine, [1,8] naphthyridines-4-base amine, [1,5] naphthyridines-4-base amine and [1,8] naphthyridines-4-base amine, pyrido [2,3-b] pyrazine-8-base amine belongs within the scope of quinolyl-4 amine analog.
" pharmaceutically acceptable salt " is commonly considered as in this skill being applicable to that the tissue with the mankind or animal contacts, and can not cause excessive toxicity, the acid of zest, anaphylaxis or other problem or complication or alkali salt class.These salts comprise as the mineral acid and the organic acid salt of tool alkaline residue (as amine), and as: the alkali metal or the organic salt of tool acidic residues (as carboxylic acid).Clear and definite pharmaceutical salt includes, but is not limited to, acid as: hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic, fumaric acid, sulphuric acid, amine sulfonic acid, sulfanilic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethionic acid, 2-ethylenehydrinsulfonic acid, nitric acid, benzoic acid, 2-acetoxy-benzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, salicylic acid, glutamic acid, ascorbic acid, pamoic acid, succinic acid, fumaric acid, maleic acid, propanoic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, alkanoic acid class are as acetic acid, HOOC-(CH
2)
n-COOH, wherein n is 0 to 4, or the like.Similarly, pharmaceutically acceptable cation includes, but is not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.Practise other pharmaceutically acceptable pattern of the salty understanding chemical compound that this paper provides of personage of this related art techniques, comprise that they list in Remington:The Science andPractice of Pharmacy, the 21st edition, Lippincott Williams ﹠amp; Wilkins, Philadelphia, the salt among the PA (2005).Generally speaking, pharmaceutically acceptable acid or alkali salt can be made according to any known chemical method by the parent compound that comprises alkalescence or acid partly group.In brief, the method for making of these salts can be with free acid or the pattern of alkali and the suitable alkali or the acid of stoichiometry of these chemical compounds, in water or organic solvent, or reaction and preparing in the two the mixture in this; Usually use non-aqueous media, as: ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile are preferable.
Salty understanding, each chemical compound of formula I can, but unnecessary, filling a prescription is hydrate, solvate or non-covalent mistakeization thing.In addition, multiple different crystal type and polymorphic isomeric compound (polymorph) are all within the scope of the present invention.This paper also provides formula I chemical compound medicine before." prodrug " not necessarily meets the chemical compound that this paper is provided the structural formula of compound requirement fully by a kind of, but can be after the patient is given in throwing, and in vivo modifying, production I or this paper provide the chemical compound of other chemical formula.For example: prodrug can be the acylated derivatives of chemical compound that this paper provides.Prodrug comprises wherein hydroxyl, amine or the chemical compound of sulfydryl bond on any group, after mammalian subject is given in throwing, can distinguish cracking and form free hydroxyl group, amido or sulfhydryl.The prodrug example includes, but is not limited to: the amine functional group in the phosphoric acid of acetic acid, formic acid, ethanol and benzoic acid derivative and the chemical compound that this paper provided.But the functional group before the chemical compound that this paper provides in the medicine method for making modified compound makes it cleavable and forms parent compound.
Term that this paper adopts " alkyl " refers to that the saturated fat of straight chain or branched chain is a hydrocarbon.Alkyl comprises having 1 to 8 carbon atom (C
1-C
8Alkyl), 1 to 6 carbon atom (C
1-C
6Alkyl) with 1 to 4 carbon atom (C
1-C
4Alkyl) group, as: methyl, ethyl, propyl group, isopropyl, normal-butyl, second butyl, tributyl, amyl group, 2-amyl group, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methyl amyl." C
0-C
nAlkyl " refers to single covalent bond (C
0) or the alkyl of 1 to n carbon atom of tool; " C
0-C
4Alkyl " refers to single covalent bond or C
1-C
4Alkyl." C
0-C
8Alkyl " refers to single covalent bond or C
1-C
8Alkyl.Some examples in this article particularly point out the substituent group of alkyl.For example, " C
1-C
6The cyano group alkyl " mean and have the substituent C of at least one CN
1-C
6Alkyl.A cyanoalkyl group of representational branch is C (CH
3)
2CN.C similarly, "
1-C
6Hydroxy alkyl " mean and have the substituent C of at least one OH
1-C
6Alkyl.
" stretch alkyl " and refer to divalent alkyl as above-mentioned definition.C
0-C
3Stretching alkyl is single covalent bond or the alkyl of stretching with 1,2 or 3 carbon atom; C
0-C
4Stretching alkyl is single covalent bond or the alkyl of stretching with 1 to 4 carbon atom; And C
1-C
6Stretching alkyl is single covalent bond or the alkyl of stretching with 1 to 6 carbon atom.
" thiazolinyl " refers to straight chain or branched chain thiazolinyl, wherein contains at least one unsaturated carbon-to-carbon double bond.Thiazolinyl comprises C
2-C
8Thiazolinyl, C
2-C
6Thiazolinyl and C
2-C
4Thiazolinyl, it contains 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively, as: vinyl, pi-allyl or isopropenyl." alkynyl " refers to straight chain or branched chain or ring-type alkynyl, and it comprises one or more unsaturated carbon-carbon bonds, and wherein at least one is the ginseng key.Alkynyl comprises C
2-C
8Alkynyl, C
2-C
6Alkynyl and C
2-C
4Alkynyl, it contains 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively.
" cycloalkyl " is for comprising one or more full and/or groups of saturated rings partly, wherein all ring group members are carbon, as: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, adamantyl, decahydro naphthyl, octahydro indenyl, and as the above-mentioned saturated group of part, as: cyclohexenyl group.Cycloalkyl does not comprise aromatic rings or heterocycle.Some cycloalkyl is C
3-C
7Cycloalkyl, its medium ring comprise 3 to 7 ring group members, and all ring group members are carbon." (C
3-C
8Cycloalkyl) C
0-C
6Alkyl " be via single covalent bond or C
1-C
6Stretch 3 to 8 Yuans cycloalkyl of alkyl binding.
This paper adopts " alkoxyl " to refer to utilize the oxygen bridging group attached as above-mentioned alkyl.Alkoxyl comprises C
1-C
6Alkoxyl and C
1-C
4Alkoxyl, it contains 1 to 6 or 1 to 4 carbon atom respectively.The alkoxy grp of representativeness is methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, second butoxy, the 3rd butoxy, n-pentyloxy, 2-amoxy, 3-amoxy, isoamoxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methyl amoxy.
Similarly, " alkylthio group " refer to via disulfide-bridged base attached as above-mentioned alkyl.
Term " ketone group " is used for this paper middle finger ketone (keto) base (C=O).For the substituent ketone group of non-aromatic series carbon atom causes making-CH
2-change into-C (=O)-.
Term " alkanoyl " refer to carbon atom wherein be the acyl group of straight chain or branch's arrangement (for example :-(C=O)-alkyl).Alkanoyl has the carbon atom of institute's reference numerals, and the carbon of its ketone groups is included in this carbon atom number that indicates.C for example
2Alkanoyl is for having the CH of formula-(C=O)
3Acetyl group.Alkanoyl comprises, for example: C
2-C
8Alkanoyl, C
2-C
6Alkanoyl and C
2-C
4Alkanoyl, it contains 2 to 8,2 to 6 or 2 to 4 carbon atoms respectively." C
1Alkanoyl " refer to-(C=O)-and H, it is (with C
2-C
8Alkanoyl) includes at term " C
1-C
8Alkanoyl " scope in.
" alkane ketone " is the ketone group of straight chain or branch's alkyl arrangement for carbon atom wherein." C
3-C
8Alkane ketone ", " C
3-C
6Alkane ketone " with " C
3-C
4Alkane ketone " refer to have 3 to 8 respectively, to 6 or to the alkane ketone of 4 carbon atoms.For example: C
3The structural formula of alkane ketone group is-CH
2-(C=O)-CH
3
Similarly, " alkyl ether " refers to straight chain or branch's ether substituent group (that is warp is with alkyl group of alkoxyl replacement).Alkyl ether groups comprises C
2-C
8Alkyl ether, C
2-C
6Alkyl ether and C
2-C
4Alkyl ether, it has 2 to 8 respectively, to 6 or to 4 carbon atoms.C
2The structural formula of alkyl ether is-CH
2-O-CH
3
Term " alkoxy carbonyl " refers to that (that is formula is-C (=O)-group of O-alkyl) by the attached alkoxyl of ketone ((C=O)-) bridge.Alkoxy carbonyl comprises C
1-C
8, C
1-C-
6With C
1-C
4Alkoxy carbonyl, its alkyl partly have 1 to 8 respectively, to 6 or to 4 carbon atoms (that is the carbon of ketone bridge is not included in the number of the carbon atom that is indicated)." C
1Alkoxy carbonyl " mean-C (=O)-O-CH
3C
1Alkoxy carbonyl means-C (=O)-O-(CH
2)
2CH
3Or-C (=0)-O-(CH
2)
2CH
3
This paper adopts " alkanoyloxy " to refer to utilize the alkanoyl of oxygen bridging group binding, and (that is formula is-O-C (=O)-group of alkyl).Alkanoyloxy comprises C
2-C
8, C
2-C
6With C
2-C
4Alkanoyloxy, its alkyl partly have 2 to 8 respectively, to 6 or to 4 carbon atoms.For example, " C
2Alkanoyloxy " mean-O-C (=O)-CH
3
" alkyl sulphonyl " refers to formula-(SO
2The group of)-alkyl, wherein attachment point is a sulphur atom.Alkyl sulphonyl comprises C
1-C
6Alkyl sulphonyl and C
1-C
4Alkyl sulphonyl, it has 1 to 6 or 1 to 4 carbon atom respectively.Methyl sulphonyl is the alkane sulfonyl of a representativeness.
" alkyl amine group " refer to formula be the NH-alkyl or-secondary or the tertiary amine of N (alkyl) (alkyl), wherein each alkyl can be independently selected from alkyl, cycloalkyl and (cycloalkyl) alkyl.These groups for example comprise: single-with two-(C
1-C
8Alkyl) amido, wherein each C
1-C
8Alkyl can be identical or different and can contain 1 to 8 carbon atom, and single-with two-(C
1-C
6Alkyl) amido with single-with two-(C
1-C
4Alkyl) amido is as the same.
" alkyl amine group alkyl " refer to utilize the alkyl amine group stretch alkyl bindings (that is have formula be-stretch alkyl-NH-alkyl or-stretch the group of alkyl-N (alkyl) (alkyl)), wherein each alkyl for be independently selected from alkyl, cycloalkyl reaches (cycloalkyl) alkyl.The alkyl amino alkyl comprises, for example: single-with two-(C
1-C
8Alkyl) amido C
1-C
8Alkyl, list-with two-(C
1-C
6Alkyl) amido C
1-C
6Alkyl with single-with two-(C
1-C
6Alkyl) amido C
1-C
4Alkyl." single-or two-(C
1-C
6Alkyl) amido C
0-C
6Alkyl " refers to utilize single covalent bond or C
1-C
6Stretch alkyl link single-or two-(C
1-C
6Alkyl) amido C
0-C
6Alkyl.Representative alkyl amine group alkyl is as follows:
Salty understanding is at term " alkyl amino " with " the alkyl amino alkyl " used " alkyl " definition with other contains in the alkyl group used at all " alkyl " and definition different, and at cycloalkyl and included scope (for example, (C of (cycloalkyl) alkyl
3-C
7Cycloalkyl) C
0-C
6Alkyl).
As used in this article, " (4 to 7 element heterocycle alkyl) amino " mean formula-N (R) group (R), one of them R is 4 to 7 element heterocycle alkyl rings and another R is hydrogen or C
1-C
6Alkyl.
Term " amido carbonyl " refer to amide group (that is-(C=O) NH
2).Term " single-or two-(C
1-C
6Alkyl) amido carbonyl " refers to formula-(C=O)-N (R)
2Group, wherein carbonyl is an attachment point, a R is C
1-C
6Alkyl and another R are hydrogen or the independent C that selects
1-C
6Alkyl.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
" haloalkyl " is the alkyl that halogen replaced (for example: " the halo C through one or more independent selections
1-C
8Alkyl " has 1 to 8 carbon atom; " halo C
1-C
6Alkyl " have 1 to 6 carbon atom).The haloalkyl example includes, but is not limited to: single-, two-or three-methyl fluoride; Single-, two-or three-chloromethyl; Single-, two-, three-, four-or five-fluoro ethyl; Single-, two-, three-, four-or-the pentachloro-ethyl; With 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl.Typical case's alkylhalide group is trifluoromethyl and difluoromethyl.Term " halogen alkoxyl " refer to utilize oxo bridge attached as the defined haloalkyl of preamble." C
1-C
8Halogenated alkoxy " has 1 to 8 carbon atom." halogenated alkyl sulfonyl " mean utilization-SO
2The haloalkyl that-bridge is attached." C
1-C
6Halogenated alkoxy " has 1 to 6 carbon atom.
Weak point broken line between two letters or code name (" ") is the attachment point that is used to represent substituent group.For example :-CONH
2System utilizes carbon atom attached.
" carbocyclic ring " or " carbocylic radical " comprises at least one ring that is formed by carbon-carbon bond fully (being referred to herein as carbocyclic ring) and do not contain heterocycle.Except as otherwise noted, otherwise each carbocyclic ring in the carbocyclic ring can be saturated, saturated or aromatic series person partly independently.Carbocyclic ring have usually 1 to 3 condense, the ring of side joint or spiral shell; Carbocyclic ring in some specific embodiment can have a ring or two fused rings.Typically, each ring comprises 3 to 8 ring group member (that is C
3-C
8); C
5-C
7Ring then appears in some specific embodiment.Comprise condense, the carbocyclic ring of side joint or volution typically comprises 9 to 14 ring group members.Some carbocyclic ring is C
5-C
6(that is, contain 5 to 6 ring persons).Some representative carbocyclic ring is as above-mentioned cycloalkyl.Other carbocyclic ring is aryl (that is comprise at least one aromatic series carbocyclic ring, this ring has or do not have extra aromatic series ring and/or naphthenic ring).These aryl carbocyclic rings comprise, for example: phenyl, naphthyl (for example, 1-naphthyl and 2-naphthyl), Fluorene base, indenyl and 1,2,3,4-tetrahydrochysene-naphthyl.C
6-C
10Aryl C
0-C
8Alkyl comprises by direct bond for they's carbocyclic ring wherein or sees through C
1-C
8At least one aromatic rings of alkyl institute binding.This group is to comprise, for example, and phenyl and indenyl, and above-mentioned arbitrary group is via C
1-C
8Alkyl (is preferably via C
1-C
4Alkyl) group that connects.Other carbocyclic ring is (C
3-C
8Carbocyclic ring) C
0-C
4Alkyl (that is wherein 3 to 8 Yuans carbocyclic rings are carbocyclic rings of stretching the alkyl binding via single covalent bond or C1-C4).For example, the phenyl via direct bond or alkyl connect can be designated as phenyl C
0-C
8Alkyl (for example, benzyl, 1-phenyl-ethyl, 1-phenyl-propyl group and 2-phenyl-ethyl).
" heterocycle " or " heterocyclic radical " have 1 to 3 condense, the ring of side joint or spiral shell; Wherein at least one is heterocycle (that is one or more annular atoms for independently being selected from the hetero atom of O, S, N, all the other annular atomses are carbon).Typically, heterocycle comprises 1,2,3 or 4 hetero atom; In some specific embodiment, each ring has 1 or 2 hetero atom in each heterocycle.Each heterocycle comprise usually 3 to 8 ring group members (showing rings in some specific embodiment) with 4 or 5 to 7 ring group members contain with the typical case condense comprising of 9 to 14 ring group members, the heterocycle of the ring of side joint or spiral shell.Some heterocycle comprises sulphur atom as the ring group member; In some specific embodiment, sulphur atom is through being oxidized to SO or SO
2Heterocycle can be optionally through multiple, as specified, substituent group replace.Except as otherwise noted, otherwise heterocycle can be Heterocyclylalkyl (that is each ring is for saturated or partly saturated) or heteroaryl (that is at least one ring is aromatic series in the group), as 5 to 10 Yuans heteroaryls (it can be monocycle system or bicyclic ring system) or 6 Yuans heteroaryls (for example, pyridine radicals or pyrimidine radicals).But any annular atoms of the general mat of heterocycle links, so that stable finished product chemical compound to be provided.The heterocycle base system of N-binding utilizes it to form the nitrogen-atoms binding.
Heterocyclic radical for example comprises: the perhydro a word used for translation is exhaled base (azepanyl), a word used for translation
Base (azocinyl), benzimidazolyl, benzimidazoline base, benzisothiazole base, benzisoxa
Azoles base, benzofuranyl, benzimidazole thiophanate are for furyl, benzo
Azoles base, benzothiazolyl, benzo tetrazole radical,
Base,
Thiazolinyl, cinnolines base, decahydroquinolyl, dihydrofuran be [2,3-b] tetrahydrofuran base, dihydro-isoquinoline base, dihydro tetrahydrofuran base, 1 also, 4-two oxa-s-8-azepine-spiral shell [4.5] decyl, two thiophenes
Base, furyl, furan Xanthones base, imidazolinyl, imidazolidine base, imidazole radicals, indazolyl, indole thiazolinyl, indoline base, Yin
Base, indyl, isobenzofuran-base, different
Base, iso indazolyl, isoindoline base, isoindolyl, isothiazolyl, different
Azoles base, isoquinolyl, morpholinyl,
Pyridine base, octahydro isoquinolyl,
Di azoly,
Azoles pyridine base,
Azoles base, dai
Base, piperazine
Base, piperidyl, piperidone base, pteridyl, purine radicals, pyranose, pyrrole
Base, pyrazoles pyridine base, pyrazolinyl, pyrazolyl, clatter
Base, pyridine-imidazole base, pyrido
Azoles base, pyrido thiazolyl, pyridine radicals, pyrimidine radicals, Pyrrolizidine base, Pyrrolizidine ketone group, pyrrolinyl, pyrrole radicals, quinazolyl, quinolyl, quinoline
Quinoline base, quininuclidinyl, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, thiophene two
Base, thiadiazolyl group, thiazolyl, thieno thiazolyl, thieno
Azoles base, Thienoimidazole base, thienyl, thienyl (thiophenyl), thio-morpholinyl (with sulphur atom wherein through the variation group of oxidation), three
Base, with as this paper is illustrated states any group on 1 to 4 substituent group replacement.
Some heterocyclic radical is that to contain be 1 heterocycle that need be substituted or 2 fused rings or 4 to 10 members of volution, 5 to 10 members, 3 to 7 members, 4 to 7 Yuans or 5 to 7 element heterocycle bases.4 to 10 element heterocycle alkyl comprise that for example: piperidyl, piperazinyl, pyrrolidinyl, a word used for translation Boom base, 1,4-two
-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, N-morpholinyl, N-thio-morpholinyl and 1,1-two
-thiomorpholine-4-base.These groups can be as being substituted of being indicated.Representational heteroaromatic is a word used for translation mouth octyl group, pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical and 3,4-dihydro-1H-isoquinolin-2-base.C
3-C
10Heterocyclylalkyl comprises that for example: piperidyl, piperazinyl, pyrrolidinyl, a word used for translation Boom base, 1,4-two
-8-a word used for translation-spiral shell [4.5] last of the ten Heavenly stems-8-base, N-morpholinyl, N-thio-morpholinyl and 1,1-two
-thiomorpholine-4-base, and wherein each aforementioned group is the group that is substituted.Representational heteroaromatic is a word used for translation mouth octyl group, pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical and 3,4-dihydro-1H-isoquinolin-2-base.
" heterocycle C
0-C
6Alkyl is " for utilizing single covalent bond or C
1-C
6Stretch the heterocycle of alkyl binding.(3 to 10 element heterocycle) C
0-C
6Alkyl is for utilizing 3 to 10 element heterocycles of stretching the alkyl binding of 1 to 6 carbon atom of tool.(4 to 7 element heterocycle) C
0-C
4Alkyl is to utilize single covalent bond or C1-C4 to stretch 4 to 7 zooid's heterocycloalkyl rings of alkyl binding.
This paper adopts " substituent group " to refer to the molecule part group of atom in the extremely interesting molecule of covalency bond.For example: " ring substituents " can be as: the part group of halogen, alkyl, haloalkyl or other group, this part group covalency bond is to the atom (being preferably carbon atom or nitrogen-atoms) that is ring person.The general covalency bond of aromatic substituents is to ring carbon atom.Term " replacement " refer to use as above-mentioned substituent group displacer molecule structure in hydrogen atom, but can not surpass valence mumber on the specified atom, and method of substitution obtains chemically stable chemical compound (that is can be singly from, judge its characteristic and test its biological activity) thus.
The group that " can choose wantonly and be substituted " is typically 1,2,3,4 or 5 position for being unsubstituted or being substituted in one or more positions that utilize through hydrogen one or more proper group (it can be identical or different) in addition.Can choose replacement wantonly also with the syntactic representation of " replacing through 0 to X substituent group ", wherein X is spendable substituent maximum number.Some can choose the group system that is substituted wantonly through 0 to 2, to 3 or replace (that is be unsubstituted or through to the maximum substituent group number replacement of nearly being shown) to 4 substituent groups of independently selecting respectively.Other optional group that is substituted is for through at least one substituent group (for example, through from 1 to 2, to 3 or replace to 4 substituent groups of independently selecting).
Term " VR1 " exchanges use in this article with " capsaicin receptor ", refers to the 1st type class cephrol receptor.Except as otherwise noted, otherwise these terms (for example: GenBank accession number AF327067, AJ277028 and NM_018727 comprise rat and human VR1 receptor; Some human VR1cDNAs and coded aminoacid sequence are by United States Patent (USP) case No.6, and 482,611 provide), and its congener of in other species, finding.
" VR1 regulator " also is referred to herein as " regulator ", is a kind of chemical compound of regulating the information conduction of VR1 activation and/or VR1-mediation.The VR1 regulator that this paper clearly provided is the pharmaceutically acceptable salt of formula I chemical compound and formula I chemical compound.The VR1 regulator can be VR1 agonist or antagonist.The K that some regulator combines with VR1
iLess than 1 little not ear concentration, be preferably less than, 500 Nai Moer concentration, 100 Nai Moer concentration, 10 Nai Moer concentration or 1 Nai Moer concentration.This paper example 5 is for measuring the K of VR1
iRepresentative analytical test.
If regulator is showing and is suppressing that class cephrol ligand combine with VR1 and/or information that VR1-mediates conducts that (employing for example: the representative analytical test that example 6 is provided), then these regulators are considered as " antagonist "; Usually these antagonisies suppress the IC of VR1 activation in the analytical test that example 6 is provided
50Value is preferably less than 500 Nai Moer concentration less than 1 little not ear concentration, is preferably less than 100 Nai Moer concentration, less than 10 Nai Moer concentration or 1 Nai Moer concentration.The VR1 antagonist comprises neutral antagonist and anti-agonist.
VR1 it " anti-agonist " makes the activity of VR1 reduce to its basis activity with the purgation chemical compound for when not adding class cephrol ligand.The anti-agonist of VR1 also can suppress the activity of class cephrol ligand to VR1, and/or also can suppress class cephrol ligand and combine with VR1.The basis of VR1 is active and because of the existence of VR1 antagonist causes the reduction of VR1 activity, can adopt calcium to move analytical test and measure, as the analytical test of example 6.
VR1 it " neutral antagonist " is the activity of a kind of inhibition class cephrol ligand to VR1, but can not show the chemical compound that changes receptor basis activity (that is moves in the analytical test at example 6 described calcium, when not having class cephrol ligand to exist, the active reduction degree of VR1 is no more than 10%, be more preferred from and be no more than 5%, even be more preferred from and be no more than 2%; Best activity decline) for not having to detect.The neutral antagonist of VR1 can suppress class cephrol ligand and combine with VR1.
This paper adopts " capsaicin receptor agonists " or " VR1 agonist " to surpass the chemical compound (that is the message that mediated of reinforcement VR1 activation and/or VR1 is conducted) of basis activity of receptor by a kind of activity of raising receptor.The representative analytical test that the capsaicin receptor agonists activity can adopt example 6 to be provided is differentiated.Generally speaking, these agonists in the analytical test that example 6 is provided, EC
50Value is preferably less than 500 Nai Moer concentration less than 1 little not ear concentration, is preferably less than 100 Nai Moer concentration, is more preferred from less than 10 Nai Moer concentration.
" class cephrol " is capsaicin or any chemical compound that comprises benzyl ring, and these phenyl ring are to utilize two oxygen atoms and the adjacent ring carbon atom bond (attachment point of the 3rd of institute's bond the part group is para-position on one of them carbon atom and the phenyl ring).Capsaicin is a kind of representational class cephrol." class cephrol ligand " is a kind cephrol, if its Ki that combines with VR1 (measuring according to the illustrated method of this paper) is no more than 10 μ m.Class cephrol ligand agonist comprises capsaicin, Ovani (olvanil), N-arachidonic acyl group-dopamine and resin toxin (resiniferatoxin) (RTX).Class cephrol ligand antagonist comprises capsaicin nitrogen Boom (capsazepine) and iodo resin toxin.
" treatment effective dose " (or dosage) is for when throwing when giving the patient, the consumption during to patient's benefit (for example: at least a symptom of receiving treatment is being shown alleviate) of the identification that begins.These alleviate degree and can adopt any proper standard to detect, and comprise and relax one or more symptoms for the treatment of, as: pain.Treatment effective dose or dosage can make the middle compound concentration of body fluid (as: blood, blood plasma, serum, cerebrospinal fluid (CSF), synovial fluid, lymph fluid, interstitial cell fluid, tear or urine) be enough to change the in vitro associativity (analytical test of adopting example 5 to be provided) of class cephrol ligand and VR1 and/or the information conduction (analytical test of adopting example 6 to be provided) that VR1 mediated usually.The cognizable patient of salty understanding benefits and can manifest after the throwing of single dose is given, or can manifest after the several throwing of treatment effective dose is given, and it is to depend on that each description of throwing the chemical compound that gives is according to determining the course of treatment that is predetermined that its throwing is given.
" statistically evident " used herein is meant from the control group and changes the result of p＜0.1 at least.Significant degree is as the canonical parameter analytical test of using statistically significant such as student T test.
" patient " provided any individuality of compounds for treating by accepting this paper.The patient comprises the mankind, and other animal is as house pet (for example: Canis familiaris L. and cat) and domestic animal.The patient may suffer from change one or more symptoms that capsaicin receptor regulating action is responded (for example: pain, be exposed to class cephrol ligand, scratch where it itches, urinary incontinence, overactive bladder, breathing pathological changes, cough and/or singultus), maybe may not have these symptoms (that is treatment can be thinking that it is preventative person that the patient of the risk that develops these symptoms is arranged).
Pyridazinyl quinolyl-4 amine that is substituted and pyrimidine radicals quinolyl-4 amine analog
As above-mentioned, the invention provides the pyridazinyl quinolyl-4 amine and the pyrimidine radicals quinolyl-4 amine analog that are substituted, it can be used for many aspects, comprises that treatment pain is (for example: the neural pain that is mediated of neurogenic or periphery); Be exposed to capsaicin; Be exposed to acid, heat, light, tear gas, air pollutants (as, for example: medicated cigarette), infectiousness preparation (comprising virus, antibacterial and yeast), pepper spray or related preparations; Respiratory symptom as: asthma or chronic obstructive pulmonary disease; Scratch where it itches; Urinary incontinence or overactive bladder; Cough or singultus; And/or it is fat.These chemical compounds (for example: the receptor active analytical test), as the probe of detecting and location VR1, reach the reference material as ligand associativity and message that VR1 mediates conduction analytical test also can be used in vitro analytical test.
In the chemical compound of some formula I or formula that other this paper provides, Z and/or Y are that (for example, Z is N and Y is CR to N
1, Y is N and Z is CR
1Or Z and Y are N).In other chemical compound, Y is CH (for example, Y wherein and Z are the chemical compound of CH).
Ar
1Be phenyl or 6 Yuans heteroaryls in some chemical compound that is provided of this paper, these groups 0 to 3 substituent group of respectively hanging oneself replaces, and it is LR that described substituent group is independently selected from (a) general formula
aGroup, or (b) form optional condensed 5 to 7 element heterocycles that are substituted together, described heterocycle replaces through 0 to 3 substituent group that is independently selected from Rb.These Ar groups comprise phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl respectively, and it respectively replaces through 0,1 or 2 aforesaid substituent group.In some instantiation, these substituent groups are that the position is at 6 Yuans Ar
2The para-position position.Optional Ar
2Substituent group is person as mentioned before, and comprises, for example, and halogen, hydroxyl, cyano group, amino, C
1-C
6Alkyl, C
1-C
6Haloalkyl, C
1-C
6Hydroxy alkyl, C
1-C
6Alkyl ether, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
1-C
6Alkanoyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Halogenated alkyl sulfonyl, C
1-C
6Alkyl sulfonyl amino, C
1-C
6Haloalkyl sulfonamido, list-or two-(C
1-C
6Alkyl) amino or 3 to 10 element heterocycle alkyl.Preferred Ar substituent group comprises halogen, cyano group, C
1-C
6Alkyl, C
1-C
6Haloalkyl, C
1-C
6Hydroxy alkyl, C
1-C
6Cyano group alkyl, C
1-C
6Alkoxyl, C
1-C
6Halogenated alkoxy, C
1-C
6Alkyl ether, C
1-C
6Alkanoyl, C
1-C
6Alkyl sulphonyl, C
1-C
6Halogenated alkyl sulfonyl, amino, list-or two-(C
1-C
6Alkyl) amino or 5 or 6 element heterocycle alkyl.In some these chemical compound, Ar is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, and it respectively replaces through 0,1 or 2 substituent group that independently is selected from following person: halogen, cyano group, amino, C
1-C
4Alkyl, C
1-C
4Hydroxy alkyl, C
1-C
4Cyano group alkyl, C
1-C
4Alkoxyl, C
1-C
4Alkanoyl, C
1-C
4Haloalkyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Halogenated alkyl sulfonyl, list-or two-(C
1-C
4Alkyl) amino or 5 or 6 element heterocycle alkyl.
In the chemical compound that some this paper provided, R
2Be hydrogen, halogen, C
1-C
6Alkyl, C
4-C
7Cycloalkyl, C
2-C
6Alkyl ether, list-or two-(C
1-C
6Alkyl) amino, morpholinyl C
0-C
2Alkyl, pyrrolidinyl C
0-C
2Alkyl, piperazinyl C
0-C
2Alkyl, piperidyl C
0-C
2Alkyl or azetidinyl C
0-C
2Respectively hang oneself 0 to 4 substituent group of alkyl, above group replaces, and described substituent group is independently selected from halogen, cyano group, hydroxyl, amino, ketone group, list-or two-(C
1-C
6Alkyl) amino, C
1-C
6Alkyl or C
1-C
6Haloalkyl.Representational R
2Be hydrogen, halogen, C
1-C
4Alkyl or C
1-C
4Alkyl ether.
R
3In some chemical compound, be hydrogen.
R
3In some chemical compound that this paper provided, be hydrogen, cyano group, C
1-C
6Alkyl, C
1-C
6Halogen substituted alkyl, C
1-C
6Alkoxyl or C
1-C
6Halogen is for alkoxyl.Representational R
4Ji Mission Bao Kuo Halogen element, cyano group, methyl and trifluoromethyl.
R
5Be independently to be selected from hydrogen, halogen, cyano group, C when occurring in some chemical compound that this paper provided at every turn
1-C
6Alkyl, C
1-C
6Haloalkyl, C
1-C
6Alkoxyl or C
1-C
6Halogenated alkoxy.In a minor, be denoted as R
5Substituent group just have one for hydrogen.In another minor, each R
5Be hydrogen.
In specific compound, B is CR
8, and R
8Be (i) hydrogen, hydroxyl, cyano group, amino carbonyl or COOH; Or (ii) C
1-C
8Alkoxyl, C
1-C
8Halogenated alkoxy, C
1-C
8Alkanoyl, list-or two-(C
1-C
8Alkyl) amino, 4 to 7 element heterocycle alkyl or (4 to 7 element heterocycle alkyl) amino, more than (ii) group respectively hang oneself 0 to 2 and independently be selected from following substituent group and replace:
(a) hydroxyl, halogen, cyano group, amino, amino carbonyl or COOH; Or
(b) C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
1-C
6Haloalkyl, (C
3-C
7Cycloalkyl) C
0-C
4Alkyl, C
1-C
6Alkoxyl, C
1-C
6Alkoxy carbonyl, C
2-C
6Alkyl ether, list-or two-(C
1-C
6Alkyl) amino C
0-C
2Alkyl, list-or two-(C
1-C
6Alkyl) amino carbonyl, or (4 to 7 element heterocycle) C
0-C
4Alkyl, above group are respectively hung oneself 0 to 2 and independently are selected from hydroxyl, amino, C
1-C
4Alkyl or C
1-C
4The substituent group of alkoxyl replaces.
Representational C
8Group comprises, for example, single-or two-(C
1-C
6Alkyl) amino, piperazinyl, piperidyl and pyrrolidinyl, above group is by being unsubstituted or being replaced through a substituent group that is selected from following person: hydroxyl, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Haloalkyl, C
1-C
6Alkoxyl, (single-or two-(C
1-C
6Alkyl) C amino)
0-C
2Alkyl or (4 to 7 element heterocycle alkyl) C
0-C
2Alkyl, wherein each substituent group is preferably further through hydroxyl, C
1-C
4Alkyl or C
1-C
4Alkoxyl.
In some chemical compound, A is CR
5And R
5Be to be independently selected from Qing, Halogen element, cyano group, amino, COOH, C when occurring at every turn
1-C
4Alkyl, C
1-C
4Halogen substituted alkyl, C
1-C
4Alkoxyl, C
1-C
4Halogen is for alkoxyl or Single-or two-(C
1-C
4Alkyl) amino.
Ke accepts De Which on Hua He Wu Jin Yi Bu Full foot formula II, IIa, III or IIIa or these chemical compounds De Medical Drug of some formula I:
In the chemical compound of some formula II, IIa, III or IIIa:
Y and Z are N or CH independently; In some instantiations, Y and Z are N;
R
2Be hydrogen, halogen, C
1-C
4Alkyl or C
2-C
4Alkyl ether;
R
2Be hydrogen;
R
4Be halogen, cyano group, C
1-C
6Alkyl, C
1-C
6Halogen substituted alkyl, C
1-C
6Alkoxyl or C
1-C
6Halogen is for alkoxyl; And
R
8Be hydrogen, list-or two-(C
1-C
8Alkyl) amino, piperazinyl, piperidyl and pyrrolidinyl, above group is by being unsubstituted or being replaced through a substituent group that is selected from following person: hydroxyl, C
1-C
4Alkyl, C
1-C
4Thiazolinyl, C
1-C
4Haloalkyl, C
1-C
6Alkoxyl, (single-or two-(C
1-C
6Alkyl) C amino)
0-C
2Alkyl or (4 to 7 element heterocycle alkyl) C
0-C
2Alkyl, wherein each substituent group is preferably further through hydroxyl, C
1-C
4Alkyl or C
1-C
4Alkoxyl; And
Ar is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, and it respectively replaces through 0,1 or 2 substituent group that independently is selected from following person: halogen, cyano group, amino, C
1-C
4Alkyl, C
1-C
4Hydroxy alkyl, C
1-C
4Cyano group alkyl, C
1-C
4Alkoxyl, C
1-C
4Alkanoyl, C
1-C
4Haloalkyl, C
1-C
4Alkyl sulphonyl, C
1-C
4Halogenated alkyl sulfonyl, list-or two-(C
1-C
4Alkyl) amino or 5 or 6 element heterocycle alkyl.
Hua He Wu Jin Yi Bu Full foot formula IV or a Ge or the many Ge minor IVa to IVf of some formula I:
In formula IV and IVa to IVf
D is N or CH;
R
6Be Hydrogen, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Hydroxyalkyl base alkyl, C
1-C
4Cyano group alkyl, C
1-C
4Halogen substituted alkyl, C
1-C
4Alkyl sulphonyl or C
1-C
6Halogen substituted alkyl sulfonyl;
R
7Be Hydrogen, halogen, cyano group, amino, C
1-C
4Alkyl, C
1-C
4Hydroxyalkyl base alkyl, C
1-C
4Cyano group alkyl, C
1-C
6Alkoxyl, C
1-C
4Alkanoyl, C
1-C
4Halogen substituted alkyl, Single-or two-(C
1-C
4Alkyl) amino or 5 or 6 STAFF Miscellaneous Ring alkyl;
And other symbol as mentioned before.
In some instantiation, R
6And R
7At least one is non-hydrogen; In further instantiation, R
6And R
7Both are neither to be hydrogen.In some these chemical compound, R
6Be C
1-C
4Alkyl or C
1-C
4Haloalkyl (for example, trifluoromethyl) and/or R
7Be amino, C
1-C
6Alkoxyl, list-or two-(C
1-C
4Alkyl) amino or 5 or 6 element heterocycle alkyl.
The representative compounds that is provided includes, but not limited to they and clearly do not describe the person in embodiment 1 to 3 in this article.The chemical compound that the salty this paper of understanding clearly enumerates only is representative compounds, is not intended to limit the present invention's scope.Further, as above-mentioned, the chemical compound that all this paper provided can be free acid or alkali or exist with the form of pharmaceutically acceptable salt.In addition, the hydrate of other form such as these chemical compounds or prodrug are in particular that the present invention considers.
Aspect bright some of this Hair of Zai, pyridazinyl quinolyl-4 amine that is substituted that is substituted provided by the present invention and pyrimidine radicals quinolyl-4 amine analog can show change (adjusting) VR1 activity, it is to adopt in vitro VR1 functional analysis test determination, moves analytical test as calcium.Can adopt this isoreactivity of VR1 ligand binding analysis test Preliminary screening.This paper mentioned it " test of VR1 ligand binding analysis " is intended to the in vitro receptor binding analytical test of index standard, as: in 5 suppliers of example, and " calcium moves analytical test " (also being called " signal conduction analytical test " herein), can be according to example 6 described carrying out.In brief, can adopt the state of conflict analytical test to analyze associativity with VR1, these analytical tests be by the participant of VR1 preparation in conjunction with VR1 underlined (for example:
125I or
3H) chemical compound (for example: capsaicin receptor agonists as: RTX) and unmarked test compound constant temperature reaction.In the analytical test that this paper provided, the VR1 that is used is preferably mammal VR1, is more preferred from the mankind or rat VR1.Receptor can be through reorganization performance or performance naturally.The VR1 preparation for example can be: from the human embryos kidney cell (HEK293) of the human VR1 of reorganization performance or the film preparation of Chinese hamster ovary (CHO) cell.With showing chemical compound constant temperature when reaction of regulating class cephrol ligand and VR1 associativity, can cause decline of label binding capacity or the raising of the label amount that combine with the VR1 preparation with respect to no chemical compound existence.This decline or raising can be illustrated according to this paper, are used to determine the Ki of VR1.Generally speaking, can in these analytical tests, make the chemical compound of the label amount reduction that combines with the VR1 preparation preferable.
The VR1 Tone Festival Elixirs that some this paper provided how rub Seoul (that is, inferior little Seoul of rubbing) Concentrated degree, in inferior how to rub Seoul or low what 100 skins Seoul, 20 skins Seoul, 10 skins Seoul or the 5 skins Seoul Ke Inspection Measuring Di Tone Festival VR1 activity of rubbing of rubbing of rubbing of rubbing.
As above-mentioned, be applicable to some specific embodiment as the chemical compound of VR1 antagonist.The IC of these chemical compounds
50Value can adopt the standard calcium mobile analytical test (shown in example 6) that in vitro VR1-mediated decision.In brief, but by cell and the required compound of performance capsaicin receptor reach calcium concentration in the indicator cells indicator (for example: the calcium sensitivity dyestuff that film can be penetrating as: (the two all for example can derive from: Molecular Probes for Fluo-3 or Fura-2, Eugene, OR), when with Ca
++In conjunction with the time, can produce the fluorescent signal respectively) contact.These contacts are preferably in the solution of the buffer of one or both in inclusion compound and the indicator or culture medium, and carry out under the cell culture one or many.Contact should be kept is enough to make dyestuff to enter in the cell area of a room in (for example: 1 to 2 hour).Cell is after washing or filtering the eliminating excess dye, and with class cephrol receptor agonists (for example: capsaicin, RTX or Ovani (olvanil)), the typical case is in equaling EC
50Contact under the concentration, measure the fluorescent reaction.When the cell of contacted agonist when chemical compound as the VR1 antagonist contacts, compared at the cell that does not have to contact with agonist under the test compound, this fluorescent reaction can descend at least 20%, is preferably at least 50%, is more preferred from least 80%.This paper provides the IC of VR1 antagonist
50Be preferably less than 1 little not ear concentration, less than 100nM, less than 10nM or less than 1nM.In some Ju Body Real example, the VR1 antidote that this paper provided is waiting what IC
50The short effect Elixirs activity of chemical compound Concentrated degree Wei Zhan Now You Ke Inspection Measuring in the short effect effect De Body outer analysis Try Examination of capsicim Shou Body.Some these antidote is at the IC of 100 times of high whats
50The short effect Elixirs activity of chemical compound Concentrated degree Wei Zhan Now You Ke Inspection Measuring in the short effect effect De Body outer analysis Try Examination of capsicim Shou Body.
In other specific embodiment, preferable with chemical compound as capsaicin receptor agonists.The capsaicin receptor agonists activity is usually according to example 6 described mensuration.When cell and 1 little not ear concentration contacted as the chemical compound of VR1 agonist, this fluorescent reaction signal amount was reacted signal amount raising at least 30% than the observed fluorescent that arrives of the cell that contact with the 100nM capsaicin usually.This paper provides the EC of VR1 agonist
50Be preferably less than 1 little not ear concentration, less than 100nM or less than 10nM.
VR1 regulates activity also or can adopt the dorsal root ganglion analytical test (as described in example 7) and in vivo pain relief analytical test (as described in example 8) analysis of cultivation.This paper provides the VR1 regulator to provide at this paper that in the test of one or more functional selections the VR1 activity to be had the clear and definite effect that is showing on the statistics preferable.
In some specific embodiment, this paper provides the VR1 regulator can not regulate ligand and combining as other thin table cellular surface receptor of EGF receptor Tyrosine kinases or nAChR in fact.In other words, these regulators as the activity of the cell surface receptor of EGF receptor Tyrosine kinases or nAChR (for example: to the IC of these receptors can not suppress in fact
50Or IC
40Be preferably greater than 1 little not ear concentration, the best is greater than 10 little not ear concentration).The preferably, regulator can or not be more preferred under 10 little not ear concentration in 0.5 little not ear concentration, 1 little not ear concentration and show inhibition EGF receptor active or nAChR activity.The analytical test of measuring the cell surface receptor activity can obtain from commodity, comprises deriving from Panvera (Madison, WI) the Tyrosine kinases analysis cover group in pharmaceutical factory.
In some specific embodiment, preferable VR1 regulator is non-stability and stabilization.In other words, in the zootype of measuring pain relief (as: pattern that this paper example 8 is provided), when the consumption of VR1 regulator reaches two multiple doses of lowest dose level of abundant pain relieving, only can temporarily calm (that is the persistent period be no more than remove that pain holds time 1/2) or be preferably in the calm zootype analytical test the calm effect that showing on the statistics not (people such as employing Fitzgerald is illustrated in the method for (1988) Toxicology 49 (2-3): 433-9).The preferably when its dosage reaches 5 multiple doses of lowest dose level of abundant pain relieving, can not produce the calm effect that is showing on the statistics.Better person, this paper provide the VR1 regulator under less than the intravenous dosages of 25mg/kg (being preferably less than 10mg/kg) or under the oral dose less than 140mg/kg (be preferably less than 50mg/kg, be more preferred from less than 30mg/kg), can not produce calm effect.
If when needing, can analyze some medical character of chemical compound that this paper provides, (the oral bioavailability degree of preferred compounds should make oral dose less than 140mg/kg to include, but is not limited to oral bioavailability, be preferably less than 50mg/kg, be more preferred from less than 30mg/kg, even be more preferred from less than 10mg/kg, be more preferred from again less than 1mg/kg and reach medical valid density for chemical compound) less than 0.1mg/kg with the best, (preferred compounds is when offeing medicine to individuality with medical effective dose for toxicity, answer avirulence), side effect (side effect that preferred compounds is produced when offeing medicine to individuality with medical effective dose should be equivalent to placebo), serum proteins associativity and in vitro (the in vivo half-life of preferred compounds should allow and carry out four times a day (Q.I.D.) medication with half-life in vivo, be preferably three (T.I.D.) medications every day, be more preferred from every day twice (B.I.D.) medication and best be single medication every day).In addition, be used for via regulating central nervous system (CNS) VR1 active and VR1 regulator treatment pain may need that blood-brain barrier is had different permeability, therefore when every day oral accumulated dose reach when above-mentioned, can provide and make these regulating actions reach medical significant degree, and possessing low VR1 modifier concentration in the preferable brain simultaneously, these VR1 regulator systems are used for the treatment of neural pain (that is these dosage (for example: CSF) compound concentration that is produced should be not enough to showing adjusting VR1 activity) in brain that mediated of periphery.Can adopt the known routine analysis of related art techniques to test to analyze these character and differentiate the preferred compounds of individual applications.For example: the analytical test that is used to estimate bioavailability comprises that transhipment by human enterocyte monolayer, comprises the Caco-2 cell.The permeability of single-layered compound blood-brain barrier in human body can be predicted it through the compound concentration that throwing is given in the laboratory animal brain of chemical compound (for example: through intravenous).The serum proteins associativity can be predicted it through the albumin bound analytical test.The chemical compound half-life is to take frequency with chemical compound to be inversely proportional to.The in vitro half-life of chemical compound can be estimated by the 7 described microsome half-life analytical tests of this paper example.
As above-mentioned, preferred compounds that this paper provides is an avirulence.Generally speaking, the salty understanding of term that this paper adopts " avirulence ", it is a kind of relative definition, mean any check and approve to be used for throwing through U.S. food and drug abuse test office (" FDA ") give mammal (being preferably the mankind) or meet the standard of being formulated, can be checked and approved the material of throwing and mammal (being preferably the mankind) by FDA.In addition, splendid avirulence chemical compound can meet following one or multinomial standard usually: (1) can not suppress cell ATP in fact and produce; (2) can not show prolongation heart QT at interval; (3) can not cause apparent liver to enlarge, can not cause liver ferment essence to disengage with (4).
This paper adopts the chemical compound that can not suppress the cell ATP generation in fact for meeting the chemical compound of standard shown in the example 8.In other words, describe through ATP content in the cell of 100 these compound treatment of μ M to being detected at least 50% of ATP content in the untreated cell as example 8.In better specific embodiment, ATP content is by being detected at least 80% of ATP content in the untreated cell in these cells.
Can not show the chemical compound that prolongs heart QT interval and be a kind of makes guinea pig, minipig or Canis familiaris L. compound concentration equals EC in the serum accepting to make
50Or IC
50Dosage dispensing after, can on statistics, not show the chemical compound (by detecting ECG) that prolongs heart QT interval.In some preferred embodiment, with non-through intestinal formula or oral throwing give 0.01,0.05,0.1,0.5,1,5,10,40 or the dosage statistics of 50mg/kg on can not cause the prolongations heart QT interval that showing.
Compound concentration equals EC in the serum if laboratory Nie tooth class animal (for example: white mice or rat) acceptance every day makes
50Or IC
50Dosage dispensing after 5 to 10 days, the liver that is caused is no more than 100% o'clock of matched control group to the increase of body weight ratio, this chemical compound promptly can not cause apparent liver expansion.In the better specific embodiment of the utmost point, these dosage can not make the liver enlarged degree surpass 75% or 50% of matched control group.If (for example: in the time of Canis familiaris L.), these dosage can not increase liver the body weight ratio is surpassed 50% of pairing untreated control group, preferablely are no more than 25%, are more preferred from and are no more than 10% to adopt non-Nie tooth class animal.In these analytical tests, preferable dispensing dosage gives through intestinal formula or oral throwing with non-, comprises 0.01,0.05,0.1,0.5,1,5,10,40 or 50mg/kg.
Similarly, compound concentration equals the EC of VR1 to chemical compound in the serum if laboratory animal (for example Nie tooth class) can make in acceptance
50Or IC
50The lowest dose level double strength after, can not make 100% o'clock above pairing simulation process matched group of alanine commentaries on classics amine Enzyme (ALT) in the serum, low density cholesterol (LDH) or acid, aspartic commentaries on classics amine Enzyme (AST) concentration raising degree, then this chemical compound can not promote liver ferment substance to disengage.In the better specific embodiment of the utmost point, these dosage can not make these serum-concentrations surpass 75% or 50% of matched control group.Perhaps, if in vitro in the hepatocyte analytical test, (in vitro contact with hepatocyte and the culture medium of cultivation in or in other these solution), equaling the EC of chemical compound
50Or IC
50Concentration under, any these liver ferment amount to the culture medium of disengaging is higher than match in the cellular control unit culture medium of simulation process observed to the substrate value reach the degree that can detect, then this chemical compound can not promote liver ferment essence to disengage.In the better specific embodiment of the utmost point, as the EC of chemical compound at chemical compound
50Or IC
505 times of concentration (being preferably 10 times of concentration) time, can not make any these liver ferment amount to the culture medium of disengaging be higher than the substrate value and reach the degree that can detect.
In other specific embodiment, some preferred compounds can not equal the EC of chemical compound to VR1
50Or IC
50During concentration, suppress or bring out microsome Cytochrome P450 enzyme activity, as: CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity.
Some preferred compounds is equaling the EC of chemical compound
50Or IC
50During concentration, can not make chromosome breakage (clastogenic) (for example: adopt the test of white mice erythrocyte precursor micronucleus assay, the test of Ames micronucleus assay, the test of spiral micronucleus assay, or the like measure).In other specific embodiment, some preferred compounds can not brought out sister strand exchange (for example: in Chinese hamster ovary cell) under this isoconcentration.
As discussed below, for testing goal, but VR1 regulator label isotope or radioactivity that this paper provided.For example: have one or more atoms are different from the atomic weight or the mass number of common natural existence by atomic weight or mass number identical element displacement in the chemical compound.The isotope that this paper provides the isotope example that can occur in the chemical compound to comprise hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, as:
2H,
3H,
11C,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F with
36C1.In addition, through heavy isotope as: deuterium (that is
2When H) replacing, provide some medical advantage owing to the metabolism stability is higher, for example: increase in vivo half-life or reduction required dosage, therefore more favourable under some situation.
Be substituted the preparation of pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog
Be substituted pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog and adopt the preparation of standard synthetic method usually.Starting material can be freely: Sigma-Aldrich Corp. (St.Louis, MO) obtain, or can adopt the method preparation of having set up by body before obtaining from commodity by the commodity that the supplier provided.Some initial substance and intermediate product can prepare as described herein-and other commerce and literature reference comprise:
Following response diagram is defined as with some of other each place employing herein:
Ac
2The O acetic anhydride
AcOH acetic acid
CDCl
3The deuterate chloroform
The δ chemical transport
The DME glycol dimethyl ether
The DMF dimethyl formamide
DPPF 1,1 '-two (diphenylphosphino) ferrocene
EDCl 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
The Et ethyl
EtOH ethanol
1H NMR proton magnetic resonance (PMR)
The HPLC high performance liquid chromatography (HPLC)
The Hz hertz
The iPr isopropyl
The iPrOH isopropyl alcohol
Two (trimethyl silane) amide potassium of KHMDS
KtBuO tributyl potassium
LCMS liquid chromatography/mass spectrum
The MS mass spectrum
(M+1) or M+H quality+1
MeOH methanol
The nBuLi n-BuLi
Pd
2(dba)
3Ginseng [two inferior phenylmethylacetones] two-palladium
Pd (PPh
3)
4Four (triphenylphosphinyl) palladiums (0)
PTLC prepares the type thin layer chromatography
The THF oxolane
Xantphos 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl-xanthene
Can adopt the route of synthesis shown in the similar following response diagram, and the synthetic method known to the synthetic organic chemistry related art techniques or prepare for the salty variation synthetic method of recognizing of the scholar of consummation in this skill.Each code name system cooperates any group of the explanation of chemical compound that this paper provides in the following response diagram.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 4
Reaction scheme 5
Reaction scheme 6
Reaction scheme 7
Reaction scheme 8
Reaction scheme 9
Reaction scheme 10
Reaction scheme 11
Reaction scheme 12
Reaction scheme 13
Reaction scheme 14
Reaction scheme 15
In some specific embodiment, chemical compound can comprise one or more asymmetric carbon atoms, so different heterogeneous types can appear in chemical compound.These patterns for example can be: racemoid or optical activity type.As above-mentioned, all heterogeneous types include within the scope of the present invention.However, still may need to obtain single enantiomer (enantiomer) (that is optical activity type).The standard method for preparing single enantiomer comprises asymmetric synthesis method and racemoid segregation process.The segregation of racemoid can be used down method and reach, for example, according to usage method carry out as: in the segregation agent existence under crystallization; Or for example use chromatography: to palm property HPLC tubing string.
Body carried out radioactive label before chemical compound can use in its synthetic method and comprise at least one radiosiotope atom.Each radiosiotope be preferably carbon (for example:
14C), hydrogen (for example:
3H), sulfur (for example:
35S) or iodine (for example:
125I).The chemical compound method for making of labelling tritium also sees through in tritiate acetic acid, carries out the platinum catalyticing exchanging reaction, in the tritiate trifluoroacetic acid, carries out the acid catalysis exchange reaction; Or in tritium gas with chemical compound as being subjected to matter to carry out the heterocatalysis exchange reaction.In addition, some precursor can participate in tritium-halogen exchange reaction in tritium gas, tritium gas reduction unsaturated bond, or if it is suitable then with the tritioboration sodium reduction.The probe compound of the labelling radioactivity that the compound of labelling radioactivity can be expediently ordered by the synthetic special visitor of radiosiotope supplier.
Medical composition
The present invention also provides a kind of medical composition, and it comprises chemical compound that one or more this paper provides, and base or the excipient that can accept at least a physiology.Medical composition for example can comprise: following one or multinomial: water, buffer (for example: neutral buffered normal saline solution or phosphate buffered solution), ethanol, mineral oil, vegetable oil, Er Jia Ya Sulfone, carbohydrate (for example: glucose, mannose, sucrose or glucosan), mannitol, protein, adjuvant, polypeptide or amino acid (as: glycine), antioxidant, chelating agen (as: EDTA) or glutathion and/or antiseptic.In addition, also can (but unnecessary) comprise other active component in the medical composition that this paper provided.
Medical composition is adjustable to be used for any suitable dosing mode, for example comprises: local, oral, per nasal, internal rectum or non-ly offer medicine through the intestinal formula.Term that this paper adopts is non-to be comprised through the intestinal formula: in subcutaneous, Intradermal, blood vessel (for example: intravenous), in the intramuscular, spinal cord, intracranial, sheath and intraperitoneal injection, and any similar injection or infusion techn.In some specific embodiment, preferable to be fit to oral compositions.These compositionss for example comprise: lozenge, sugar-coated ingot, suck ingot, aqueous or oily suspensions, can spare diffusing powder or granule, emulsion, rigid or soft capsule or syrup or elixir.In other specific embodiment, medical composition of the present invention can be the allotment of lyophilization thing.Topical administration with the prescription may be suitable for some symptom (for example: be used for the treatment of skin symptom as: burn or scratch where it itches).Directly offer medicine to the prescription (intravesical dispensing) of bladder and may be suitable for treating urinary incontinence and overactive bladder.
Composition for oral administration still can comprise one or more compositions, as: sweeting agent, flavoring agent, coloring agent and/or antiseptic, so that attractive and agreeable to the taste preparation to be provided.Lozenge comprises active component and is fit to make the mixed with excipients that can accept on the physiology of lozenge.These excipient for example comprise: inert diluent (for example: calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulation agent and disintegrating agent (for example: corn starch or alginic acid), bonding agent (for example: starch, gelatin or arabic gum) and lubricant (for example: magnesium stearate, stearic acid or Talcum).Lozenge can not have coating maybe can coat coating according to known technology, to delay disintegrate and absorption in gastrointestinal tract, uses the continuous action that provides long-term.For example: up time retardance material is as glyceryl monostearate or distearin.
Prescription for oral use also can be the glutoid capsule, wherein mix (for example: calcium carbonate, calcium phosphate or Kaolin) with inert solid diluent by active component, or be soft ' Yanming ' capsules for clearing, wherein active component mixes with water or oily medium (for example: Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil).
Waterborne suspension comprises active component (group) mixing appropriate excipients and makes waterborne suspension, and they's excipient comprises: suspending agent (for example: sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and arabic gum); (for example: natural phospholipid is as lecithin with even powder or wetting agent, the condensation product of stretching trialkylphosphine oxide and fatty acid as: polyoxy is stretched ethyl stearate, the condensation product of oxirane and long-chain fat system alcohol as: 17 carbon are stretched the ethyoxyl spermol, oxirane and derived from the condensation product of the part ester of fatty acid and hexitol as the polyoxyethylene sorbitol monoleate, or oxirane and derived from the condensation product of the part ester of fatty acid and hexitol acid anhydride as: the poly-ethyl sorbitan monooleate of stretching).Waterborne suspension also for example can comprise one or more antiseptic: the ethyl ester of P-hydroxybenzoic acid or n-propyl, one or more coloring agent, one or more flavoring agents and one or more sweeting agents, as: sucrose or glucide.
The subscription of oily suspensions active component (group) can be suspended in the vegetable oil (for example: Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois) or in mineral oil as liquid paraffin.Oily suspensions can comprise thickening agent as Cera Flava, rigid paraffin or spermol.Can add as above-mentioned sweeting agent and flavoring agent, so that agreeable to the taste oral formulations to be provided.These suspensions can add antioxidant such as ascorbic acid with anticorrosion.
Be fit to the preparation waterborne suspension can spare diffusing property powder and granule can make active component mix with even powder or wetting agent, suspending agent and one or more antiseptic by the interpolation of water.Suitable even powder or wetting agent and suspending agent example are as above-mentioned.Also can comprise other excipient as sweeting agent, flavoring agent and coloring agent.
Medical composition also can be formulated into oil-in-water (oil-in-water) emulsion.Oil phase (for example: liquid paraffin) or its mixture can be vegetable oil (for example: olive oil or Oleum Arachidis hypogaeae semen), mineral oil.Suitable emulsifying agent comprise lac (for example: arabic gum or tragacanth gum), natural phospholipid (for example: soybean lecithin, with derived from the ester of fatty acid and hexitol or ester partly), anhydride (for example: sorbitol monooleate) and derived from the part ester of fatty acid and hexitol and the condensation product of oxirane (for example: polyoxy is stretched the ethyl sorbitan monooleate).Emulsion also can comprise one or more sweeting agents and one or more flavoring agents.
Syrup and elixir can use the sweeting agent allotment, as: glycerol, propylene glycol, Sorbitol or sucrose.These prescriptions also can comprise one or more demulcent, antiseptic, flavoring agent and/or coloring agent.
Topical administration typically comprises local with base and active component (group) combination with prescription, can add or not add the extra composition that can optionally select for use.Suitable part is extensively to know in this skill with base and other composition, and salty understanding, and it can select base according to specific physical form and transfer mode.The part comprises water with base; Organic solvent is as alcohols (for example: ethanol or isopropyl alcohol) or glycerol; Glycols (for example: butanediol, isoprene glycol or propylene glycol); Fat system alcohol (for example: lanoline); The mixture of water and organic solvent, and the mixture of organic solvent is as alcohols and glycerol mixture; Based on the material of lipid as: fatty acid, acylglycerol (comprising that oils is as mineral oil, with natural or synthetic fat), phosphoglyceride, nerve sheath lipid and wax class; Based on the material of protein as collagen and gelatin; Material (comprising non-volatile and volatility) based on poly-silica: with based on the material of hydrocarbon as miniature sponge and polymeric matrix.Compositions can comprise in addition that one or more are suitable for improving the stability of the prescription of using or the composition of effectiveness, as: tranquilizer, suspending agent, emulsifying agent, viscosity are adjusted agent, gellant, antiseptic, antioxidant, dermal osmosis hardening agent, wetting agent and slow-release material.These composition examples are illustrated in the The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Remington:The Sciences and Practice of Pharmacy of Martindale, 21
StEd.Lippincott Williams ﹠amp; Wilkins, Philadelphia, PA (2005).Prescription can comprise microcapsule, as: hydroxy methocel or gelatin microcapsule, liposome, albumin microsphere bead, microemulsion, nanoparticle or rice glue capsule how.
The part can be made into multiple physics pattern with prescription and comprises, for example: solid, paste, cream, foam thing, washing liquid, gel, powder, waterborne liquid and emulsion.Its physical appearance of the pattern that these medicine can be accepted and viscosity can contained emulsifying agent and viscosity adjustment agent in prescription content control.Solid is solid usually, can't topple over, and often is deployed into bar-shaped or shaft-like or F-SP; Solid can be opaque or transparent, and it can optionally comprise solvent, emulsifying agent, wetting agent, softening agent, spice, dyestuff/coloring agent, antiseptic and other can improve or strengthen the active component of end product effectiveness.Cream and washing liquid are similar usually, and its difference is mainly at its viscosity; Washing liquid and cream the two all may opaque, translucent or clarification, often comprise emulsifying agent, solvent is adjusted agent with viscosity, reach wetting agent, softening agent, spice, dyestuff/coloring agent, antiseptic and other can improve or strengthen the active component of end product effectiveness.Gel can be made into multiple different viscosity, by dense thick or high viscosity to thin or low-viscosity.These prescriptions are as washing liquid and cream, also can comprise solvent, emulsifying agent, wetting agent, softening agent, spice, dyestuff/coloring agent, antiseptic and other can improve or strengthen the active component of end product effectiveness.Flowing fluid ratio cream, washing liquid or gel are thin, do not comprise emulsifying agent usually.Liquid topical product often comprises solvent, emulsifying agent, wetting agent, softening agent, spice, dyestuff/coloring agent, antiseptic and other can improve or strengthen the active component of end product effectiveness.
Be applicable to that local emulsifying agent with prescription comprises (but being not limited to): ionic emulsifier, spermol, non-ionic emulsifier as: polyoxy is stretched ethyl oleyl ether, PEG-40 stearate, ceteareth (ceteareth)-12, ceteareth-20, ceteareth-30, cetearyl alcohol (ceteareth alcohol), PEG-100 stearate and tristerin.Suitable viscosity adjusts agent and include, but is not limited to: protective colloid or nonionic colloid are as hydroxyethyl-cellulose, tragacanth gum, aluminium-magnesium silicate, Silicon stone, microwax, Cera Flava, paraffin and cetin.The forming method of gel combination can add gellant as chitin (chitosan), methylcellulose, ethyl cellulose, polyvinyl alcohol, polyquaternium (polyquaterniums), hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxylic polymethylene (carbomer) or ammonium glycyrrhizinate.Suitable interfacial agent includes, but is not limited to: nonionic, both sexes, ionic and anionic property interfacial agent.Local with Formulation Example as: following one or more: the diformazan silicone altogether polyhydric alcohol (dimethicone copolyol), polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, coconut monoethanolamide DEA and coconut monoethanolamide MEA, oil-based betaine, coconut monoethanolamide propyl group phosphatidyl PG-ammonium chloride (cocamidopropyl phosphatidyl PG-dimoniumchloride), with ten diester ammonium sulfate.Suitable antiseptic includes, but is not limited to: antimicrobial as: to oxybenzoic acid methyl ester (methylparaben), to oxybenzoic acid propyl ester, sorbic acid, benzoic acid and formaldehyde, and physical property tranquilizer and antioxidant are as vitamin E, sodium ascorbate/ascorbic acid and Propylgallate.Suitable wetting agent includes, but is not limited to: lactic acid and other hydroxy acid and its esters, glycerol, propylene glycol and butanediol.Suitable softening agent comprises lanolin alcohol, lanoline, lanolin derivative, cholesterol, vaseline, neopentanoic acid iso stearyl ester and mineral oil.Suitable spice and pigment include, but is not limited to: FD﹠amp; C red No. 40 and FD﹠amp; Yellow No. 5 of C.Other is suitable for local extra composition with prescription can be including (but not limited to) grinding agent, absorbent, anti-caking agent, defoamer, antistatic additive, astringent (for example: Radix Hamamelidis Mollis, ethanol and medicinal herbs collection liquid are as: the Flos Matricariae chamomillae liquid that comes together), bonding agent/excipient, buffer agent, chelating agen, film formation agent, regulator, propellant, opacifying agent, pH adjustment agent and protective agent.
The suitable part of allotment gel with the base example is: hydroxypropyl cellulose (2.1%); 70/30 isopropanol (90.9%); Propylene glycol (5.1%); With polysorbate 80 (1.9%).The suitable part of allotment foam thing with the base example is: spermol (1.1%); Stearyl alcohol (0.5%; Quaternary ammonium salt 52 (1.0%); Propylene glycol (2.0%); Alcohol 95 PGF3 (61.05%); Deionized water (30.05%); P75 hydrocarbon propellant (4.30%).All percentage ratios all by weight.
The typical way that transmits topical compositions comprises uses finger to smear; Use the physical property applicator to use as cloth, toilet paper, swab, spillikin or brush; Spray (comprising that mist, aerosol or foam spray); Dripping method; Pour into; Soak; And rinse.
Medical composition also can be made into aseptic injection aqueous or oily suspensions.Decide according to the base that used and concentration, the chemical compound that this paper provided (group) can suspend or be dissolved in the base.These compositionss can be used as above-mentioned suitable even powder, wetting agent and/or suspending agent allotment according to the known mode of related art techniques.In the base and solvent that can accept, can make water, 1,3 butylene glycol, Ringer's mixture and isotonia sodium chloride solution.In addition, can use aseptic fixed oil as solvent or suspension media.Therefore the fixedly oil of nonirritant all can use, comprise synthetic singly-or Diglyceride.In addition, fatty acid such as oleic acid see the preparation of composition for injection, and adjuvant such as local anesthetic, antiseptic and/or buffer agent dissolve in the base.
Regulator also can be formulated into suppository (for example: the per rectum dispensing is used).These compositionss can prepare through the suitable nonirritant excipient of medicament mixed, and therefore this excipient can melt to disengage medicine in rectum in being solid under the room temperature but be liquid under rectal temperature.Suitable excipient comprises, for example: cocoa butter and Polyethylene Glycol.
The form that the compositions typical case that infusion is used can be solution, suspension or emulsion provides, and these shapes are can dry powder or use known propellant (for example, dichlorodifluoromethane or Arcton 11) to throw with the form of aerosol and give.
Medical composition can be formulated into slow release or controlled release formulation (that is, act as the prescription that makes the slow release of active component (group) after dispensing, as capsule).These prescriptions can prepare according to the mode that related art techniques is extensively known and usually through for example: mouthful, rectum or hypodermic implant, or implant required target location and throw and give.Preferred prescription can provide the regulator of relative constant density to discharge; The kenel that discharges can be used the salty method change of knowing of institute in this technical field, comprise: (a) by the thickness that changes coating or composition, (b) by changing plasticizer adds in coating amount or mode, (c) by comprising extra composition, as discharge adjustment agent, (d), and (e) by one or more channels by coating are provided by the composition, granular size or the grain shape that change substrate.The amount of contained regulator depends in the slow release prescription, for example, throw the method (for example, the position of implantation) give, the speed of release and estimated the duration and the character of the symptom that will treat or prevent.
Generally speaking, therefore slow release and/or controlled release formulation comprise substrate and/or postpone disintegrate and absorb in intestines and stomach (or implantation position) also provides the coating that effect postpones or effect is lasting in one longer period.For example, the up time postpones material such as glyceryl monostearate or distearin.The coating of regulating this regulator comprises the coating that pH relies on (its can in order to release regulator) under one's belt, and comprises enteric coatings (it can be used for further along the intestines and stomach release regulator).The coating that pH relies on comprises, for example: Lac, phthalandione cellulose acetate, polyvinyl acetate phthalate ester, hydroxy-methyl cellulose phthalate ester, methacrylate copolymer and maisin.
Add or and with outside the above-mentioned medication, regulator also can add to (for example: to the non-human animal, comprise fellow creature (as: Canis familiaris L. and cat) and domestic animal for dispensing) in food or the drinking-water.When can making animal on the feed, the allotment of animal feed and drinking-water compositions absorbs an amount of compositions simultaneously.Compositions is add to the premix in feedstuff or the drinking-water, also quite convenient.
Chemical compound is thrown usually and is given medical effective dose.Preferable whole-body dose is no more than 50 milligrams of pers kilogram of body weight (for example: every day, per kilogram of body weight was about 0.001 milligram to about 50 milligrams) every day, and oral dose is generally about 5 to 20 times (for example: every day, per kilogram of body weight was 0.01 to 40 milligrams) that are higher than intravenous dispensing dosage.
Can for example depend on the amount of base combination of materials: the patient that treat, specific dispensing pattern and any other medicine of giving of throwing and changing jointly with the active component that produces single dose unit.Dosage unit comprises about 10 micrograms usually to about 500 milligrams of active component.Optimal dose can be through in this skill, extensively knowing routine test and program and setting up.
Medical composition can be packed and be used for the treatment of symptom that the VR1 regulating action is responded (for example: treatment is exposed to class cephrol ligand or other stimulus object, pain, scratches where it itches, obesity or urinary incontinence).The medical composition of packing can comprise (i) container, interior dress comprises the illustrated VR1 regulator of at least a this paper for the treatment of effective dose, and (ii) description (for example: label or package gripper page or leaf), the compositions that indication wherein includes is the symptom that the VR1 regulating action is responded that is used for the treatment of the patient.
Using method
This paper provide the VR1 regulator can in vitro with in vivo, in order to activity and the activation that changes many-sided capsaicin receptor.In some aspect, the VR1 antagonist can be used in vitro or in vivo suppressing class cephrol ligand agonist (as: capsaicin with/or RTX) and combines with capsaicin receptor.Generally speaking, the step that these methods comprise is under the existence of class cephrol ligand in aqueous solution, and capsaicin receptor contacts this paper one or more VR1 regulators are provided under the condition of other suitable ligand and capsaicin receptor combination.VR1 regulator usually its concentration is mediated message conduction (the analytical test mensuration of employing example 6) for being enough to change class cephrol ligand and VR1 in vitro associativity (adopting the analytical test of example 5 to measure) and VR1.Capsaicin receptor can be solution or suspension (for example: be contained in single from film or cell preparation in), be contained in cultivate or single from cell in.In some specific embodiment, capsaicin receptor system is by patient's neurocyte performance, and this aqueous solution is a body fluid.The preferably can throw and one or more VR1 regulators animal, and it is 1 little not ear concentration or following that its dosage should make the treatment valid density of the contained VR1 regulator of at least a body fluid in the animal body; Be preferably 500 Nai Moer concentration or following; Be more preferred from 100 Nai Moer concentration or following, 50 Nai Moer concentration or following, 20 Nai Moer concentration or following, or 10 Nai Moer concentration or following.For example: the dispensing dosage of these chemical compounds can be preferably less than 5 milligrams/kilogram less than 20 milligrams/kg body weight, in some example, less than 1 milligram/kilogram.
This paper also provides the method for the message conduction active (that is calcium conduction) of a kind of adjusting (being preferably reduction) cell capsaicin receptor.These adjusting methods can contact one or more this paper through capsaicin receptor under the condition of suitable regulator (group) and receptors bind (in vitro or in vivo) and the VR1 regulator is provided and reaches.The concentration of VR1 regulator (group) is enough to change illustrated and so on the cephrol ligand of this paper and VR1 usually and mediates the message conduction in vitro associativity and VR1.Receptor can be solution or suspension, be contained in cultivate or single from cell preparation or the cell the patient in.For example: cell can be the neurocyte that contacts in living animal.Perhaps, chrotoplast on cell can be and contacts in living animal, as: bladder epithelial cell (urothelial cell) or airway epithelial cell.The regulating action of message conduction activity can be assessed (also being called calcium mobile or flow) by detecting its influence to the calcium conductivity.The regulating action of message conduction activity also can accept this paper and provide the change of patient's symptom of one or more VR1 modulators for treatment to assess by detection (for example: pain, burn sensation, bronchoconstriction, inflammation, cough, singultus, scratch where it itches, urinary incontinence or overactive bladder).
This paper provides VR1 regulator (group) to be preferably per os or local the throwing (for example: the mankind), and when regulating VR1 message conduction activity, be present at least a body fluid of animal given the patient.In in vitro regulating the preferable VR1 modifier concentration that VR1 message conduction activity is used for this kind method is 1 Nai Moer concentration or following, be preferably 100 ear concentration or following not slightly, be more preferred from 20 ear concentration or following not slightly, and in body fluid in vivo as: the concentration in the blood is 1 little not ear concentration or following, 500 Nai Moer concentration or following, or 100 Nai Moer concentration or following.
The present invention provides a kind of method to dispose the symptom that the VR1 regulating action is responded again.Among the present invention, term " disposal " comprises the disposal and the symptom disposal of disease mitigation, it can be preventative (that is the processing before symptom takes place, to prevent, to delay or reduce the seriousness of symptom) or therapeutic (that is in symptom generation post processing, to reduce the seriousness and the persistent period of symptom).No matter the local content of class cephrol ligand, if symptom to be characterized as the capsaicin receptor activity improper, and/or, then claim this symptom " the VR1 regulating action to be responded " when if the regulating action of capsaicin receptor activity causes symptom or its remission.These symptoms comprise, for example: because of be exposed to the VR1 reactivity stimulate the symptom caused, pain, respiratory system disease as: pant, chronic obstructive pulmonary disease, scratch where it itches, urinary incontinence, overactive bladder, cough, singultus and obesity, in hereinafter illustrating in greater detail it.These symptoms can be used in standard diagnostics and the monitoring that this skill has been set up.The patient can comprise the mankind, domestication fellow creature and domestic animal, its dosage such as above-mentioned.
Treatment prescription can be decided with the specific symptoms of being treated according to the chemical compound that is used.Yet, when treating most of disease, to offer medicine every day 4 times or preferable with the purgation frequency.Usually, 2 administering modes that take second place are better to offer medicine every day, and are good especially with single dispensing every day.Be management of acute pain, the single dose that reaches valid density rapidly is necessary.Yet salty understanding, clear and definite dosage and treatment prescription to any particular patient will depend on multinomial factor, comprise the seriousness of indivedual diseases during the activity of used individual compound, age, body weight, general health situation, sex, diet, dispensing time, dosing way and drainage rate, drug combination and the treatment.Usually, use is enough to provide the lowest dose level of effective treatment preferable.Can adopt suitable treat or the prevent medical science of symptom or the treatment effectiveness of veterinary's standard monitored patient.
Because of be exposed to the capsaicin receptor reactivity stimulate the patient cause symptom comprise because of heat, light, tear gas or sour cause the individuality and the mucosa of burning be exposed to (for example: because of eat, suction or eye contact) capsaicin (for example: Fructus Capsici or pepper spray) or related stimulus thing be as the individuality of acid, tear gas, infectiousness preparation or air pollution.The symptom that is produced (can use this paper that VR1 is provided regulator, refer to the symptom of antagonist for treating especially) for example can comprise: pain, bronchoconstriction and inflammation.
Can use this paper to provide the pain of VR1 modulators for treatment to can be chronic or acute pain, include, but is not limited to: the neural pain (referring to neuropathic pain especially) that is mediated of periphery.Chemical compound that this paper provides for example can be used for treatment: mastectomy postoperative pain syndrome, deformed limb pain, phantom limb pain, the oral cavity neuropathic pain, tooth pain (toothache), artificial tooth pain (denture pain), postherpetic neuralgia, diabetic neuropathy, the neuropathy that chemotherapy causes, the reflection sympathetic nerve loses supports disease, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Ji Lan-Bai Rui (Guillain-Barre) syndrome, Bernhards disease (meralgia paresthetica), syndrome and/or the pain relevant with nerve root injury with nerve are burnt in the oral cavity, (for example comprise the pain relevant with peripheral sacred disease, neural card is pressed and brachial plexus is torn, amputation, the nervus peripheralis pathological changes comprises: two survey nervus peripheralis pathological changes, trigeminal neuralgia, atypia face pain, nerve root injury and arachnoiditis).Other neuropathic pain symptom comprises that (the reflection sympathetic nerve loses and supports disease-RSD causalgia, time symptom after the periphery nerve injury), the neuritis (comprises, for example: sciatic neuritis, the periphery neuritis, polyneuritis, ophthalmoneuritis, postfebrile neuritis, migrating neuritis, sections neuritis and tribute Bo Shi (Gombault ' s) neuritis), neuronitis, neuralgia (for example: know those situations as above-mentioned, cervico-brachial neuralgia, cranial neuralgia, the knee joint neuralgia, glossopharyngeal neuralgia, the migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, the jaw Joint neuralgia, Mo Dunshi (Morton ' s) neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Si Ludeshi (Sluder ' s) neuralgia, butterfly jaw neuralgia, supraorbital neuralgia and Vidian neuralgia), the pain relevant with operation, musculoskeletal pain, face muscle pain is waited the group, the acquired immunity insufficiency disorder is waited group's (AIDS) related neural pathological changes, the related neural pathological changes of multiple sclerosis (MS), central nervous system's pain (for example, because the pain that brain stem injury caused, sciatica and ankylosing spondylosis), spinal pain comprises the ache related of spinal cord injury.Headache comprises the pain that peripheral neural excitation is relevant, also can be according to the explanation treatment of this paper.These pain for example comprise, as: hole, burst (that is migrainous neuralgia) and shrunk type headache, migraine, temporo jaw pain and maxillary sinus pain.For example: during tendency before migraine appears in the patient, give the chemical compound prevention of migraine that this paper provides but throw immediately.Other can comprise Sha Erkeshi (Charcot ' s) pain according to the pain symptom of the illustrated treatment of this paper, intestinal tympanites pain, otalgia, pained, myalgia, ophthalmalgia, mouth jaw prosopodynia (for example, toothache), stomachache Women section pain (for example, dysmenorrhoea, dysmenorrhea, the pain relevant with cystitis, labor pains, chronic pelvic chamber pain, chronic prostatitis and endometritis), acute and chronic back pain are (for example: back pain), gout, the scar pain, pain due to hemorrhoid, dyspepsia pain, angor (angina), nerve root pain, the neuropathy of " non-painful ", concurrent local pain syndrome, coordination pain and dystopy pain-the comprise relevant pain of cancer (for example :) in the osteocarcinoma patient, the pain relevant with being exposed to venom (with inflammation) (for example: because of venom, spider bites, or sting) and wound ache related (for example: postoperative pain, incised wound pain, dampen and knochenbruch, and burn and scald pain).Other can comprise that respiratory tract disease, autoimmune disease, immunodeficiency disease, hot flush, inflammatory intestinal portion disease, GERD disease (GERD), intestinal swash hot-tempered disease and/or inflammatory intestinal portion disease as previously described according to the pain symptom of treatment described herein.
In some aspect, this paper provides the VR1 regulator to can be used for treating mechanicalness pain.Pain beyond term that this paper adopts " mechanicalness pain " the finger pain, it is for neurogenic or because of being exposed to due to heat, the cold or external chemical stimulation.Mechanicalness pain comprises the pain that physical property wound (not exposing for heat or chemical burn and/or other painful that is exposed to harmful chemical) causes as: postoperative pain and because of incised wound, contusion and knochenbruch; Toothache, artificial tooth pain; Nerve root pain; Osteoarthritis; Rheumatoid arthritis; Fibromyalgia; Bernhards disease; Backache; The pain that cancer is relevant; Angor; Carpel Tunnel Syndrome; Reach the pain that causes because of fracture, childbirth, hemorrhoid, intestinal portion flatulence, dyspepsia and menstruation.
The symptom of scratching where it itches that can treat comprise chronic eczema scratch where it itches, because of scratching where it itches of causing of hemodialysis, water because of property (aquagenic) pruritus, and it relevant with vulvar vestibulitis scratched where it itches, contact skin, sting and skin allergy.Can comprise urinary incontinence (comprising spill-over urinary incontinence, urge incontinence and stress incontinence) according to the urinary tract disease of the explanation treatment of this paper, and cross moving property or unstable bladder symptom (comprise because of vertebra cause detrusor exaggerated reflex and bladder excessive sensitivity and bladder excessive sensitivity).In some these Therapeutic Method, VR1 regulator system causes the VR1 regulator to be injected directly in the bladder via conduit or similar device dispensing.Chemical compound that this paper provides also is available as antitussive (prevent, alleviate or the compacting cough) and with the treatment that is singultus, reaches alleviating of promotion obese patient's body weight.
In others, this paper provides the VR1 regulator to can be used for relating to the symptom of inflammatory factor for treatment in the coupling treatment.These symptoms for example comprise: the autoimmune pathological changes has a pathologic autoimmune reaction that inflammation becomes branch with known, includes, but is not limited to: arthritis (referring to rheumatoid arthritis especially), chronic eczema, Crohn disease (Crohn ' s disease), lupus erythematosus, intestinal swash hot-tempered disease, tissue grafts repels and the hyperacute rejection of transplant organ.Other these symptoms comprise wound (for example: head or vertebra are hindered), cardiovascular and cerebrovascular disease and some infectious disease.
In these coupling therapies, VR1 regulator system throws with antiinflammatory agents and gives the patient.VR1 regulator and antiinflammatory agents can maybe can be offerd medicine respectively according to arbitrary order in same medical composition.Antiinflammatory agents for example comprises: on-steroidal anti-inflammatory medicine (NSAIDs), non-specificity and Cycloxygenase-2 (COX-2) specificity Cycloxygenase ferment inhibitor, gold compound, corticosteroid, amine methopterin, tumor necrosis factor (TNF) receptor antagonist, anti-TNF alpha antibody, anti--C5 antibody and white plain-1 (IL-1) receptor antagonist that is situated between.The NSAID example (for example: ADVI includes, but is not limited to ibuprofen (ibuprofen)
TM, MOTRIN
TM), Flurbiprofen (flurbiprofen) (ANSAID
TM), naproxen (naproxen) or naproxen sodium (for example: NAPROSYN, ANAPROX, ALEVE
TM), diclofenac (diclofenac) (for example: CATAFLAM
TM, VOLTAREN
TM), the combination of diclofenac sodium and misoprostol (misoprostol) (for example: ARTHROTEC
TM), fast spirit reaches (sulindac) (CLINORIL
TM),
Third
(oxaprozin) (DAYPRO
TM), diflunisal (diflunisal) (DOLOBID
TM), piroxicam (piroxicam) (FELDENE
TM), indomethacin (indomethacin) (INDOCIN
TM), etodolac salt (etodolac) (LODINE
TM), fenoprofen calcium (fenoprofencalcium) (NALFON
TM), ketoprofen (ketoprofen) (for example: ORUDIS
TM, ORUVAIL
TM), nabumetone sodium (sodium nabumetone) (RELAFEN
TM), salazosulfamide (sulfasalazine) (AZULFIDINE
TM), Tolmetin sodium (tolmetin sodium) (TOLECTIN
TM), and oxychloroquine (hydroxychloroquine) (PLAQUENIL
TM).A kind of special NSAID comprises the chemical compound that suppresses Cycloxygenase (COX) ferment; These chemical compounds comprise celecoxib (celecoxib) and rofecoxib (rofecoxib) (VIOXX
TM).NSAID comprises that still Salicylate is as acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylate (TRILISATE
TM) and disalicylic acid (DISALCID
TM) and corticosteroid as: but body pine (CORTONE
TMAcetate), Sai Meisong (dexamethasone) (for example: DECADRON
TM), medrat (methylprednisolone) (MEDROL
TM), andrographolide (PRELONE
TM), prednisolone sodium phosphate (PEDIAPRED
TM) and prednisone is (for example: PREDNICEN-M
TM, DELTASONE
TM, STERAPRED
TM).Other antibiotic medicine comprises meloxicam (meloxicam), rofecoxib (rofecoxib), celecoxib (celecoxib), relies on and examine former times (etoricoxib), parecoxib (parecoxib), penta ground former times cloth (valdecoxib) and replace profit to examine former times (tilicoxib).
In these coupling therapies, the suitable dose of VR1 regulator is usually as above-mentioned.The dosage of antiinflammatory agents and medication administration method can be referring to for example: the explanation of manufacturer in Physician ' s Desk Reference.In some specific embodiment, the required dosage when combination of VR1 regulator and antiinflammatory agents dispensing result can reduce antiinflammatory agents and will produce medical effect, that is reduce minimum medical effective dose.Therefore, in combination of the present invention or the coupling medication, the dosage of antiinflammatory agents is preferably lower than when not offeing medicine with the coupling of VR1 antagonist, the highest antiinflammatory agents dosage that manufacturer advises.When this dosage was lower than not with VR1 antagonist combination dispensing, 3/4 o'clock of the highest antiinflammatory agents dosage that manufacturer advises was better, even was more preferred from and is lower than 1/2, and splendid for being lower than 1/4, optimal dose is for being lower than 10% of maximum dose level.Salty understanding, antiinflammatory agents became divided dose and effectiveness to influence during required dosage can be made up equally when VR1 antagonist composition will reach required effect in the combination.
In some preferred embodiment, the combination of VR1 regulator and the antiinflammatory agents dispensing genealogy of law is packaged in one or more VR1 regulators and one or more antiinflammatory agents in the same packing, is divided in same packing in the different vessels or is contained in the same container for the mixture that contains one or more VR1 antagonisies and one or more antiinflammatory agents.Preferable mixing system is deployed into oral administration medicine supplying with (for example: be pill, capsule, lozenge, or the like).In some specific embodiment, comprise label in the packing, indicate these one or more VR1 regulators and one or more antiinflammatory agents system to be used for co-therapy inflammation pain symptom.
In the others, this paper provides the VR1 regulator can remove the medicine combination of pain with one or more other.Some these medicine also is above-listed antiinflammatory agents.Other these medicine is analgesic, comprises that (for example: μ, κ and/or δ) anesthetis is preferably as agonist or part agonist typical effect in one or more opioid receptor hypotypes.These medicaments comprise Opiate, Opiate derivant and class opiate, in the and pharmaceutically acceptable salt and hydrate. preferred embodiment, the clear and definite example of anesthesia-anodyne comprises A Fenta mud (alfentany1); A Fapuluting (alphaprodine); Anileridine (anileridine); Betsy acid amides (bezitramide); Buprenophine (buprenorphine); Butorphanol (butorphanol); Codeine (codeine); The diacetyl paramorphane; The diacetyl morphine; Paracodin; Diphenoxylate (diphenoxylate); The ethyl morphine; Fen Tanni (fentanyl); Hai Ruoying; But hydrogen ketone (hydrocodone); Hydrogenation hydromorphone (hydromorphone); Different methadone (isomethadone); Left-handed first all (levomethorphan); Left-handed all (levorphane); Left mutter (levorphanol); Meperidine (meperidine); Mei Suoxin (metazocine); Methadone (methadone); First all (methorphan); Methyl Dilauid (metopon); Morphine; Satisfied cloth coffee (nalbuphine); Opium extracts and thing; Opium liquid extracts and thing; The opium powder; The opium granula; Give birth to opium; The opium tincture; Hydroxyl is examined ketone (oxycodone); Numorphan Oral ketone (oxymorphone); Pa Geli (paregoric); Spray his left suffering (pentazocine); Pethidine (pethidine); Peace azoles suffering (phenazocine); Piminodine esylate (piminodine); Dextropropoxyphene (propoxyphene); Racemization first mutter (racemethorphan); Racemization mutter (racemorphan); Pharmaceutically acceptable salt and the hydrate of easypro fentanyl (sulfentanyl) thebaine (thebaine) and above-mentioned preparation.
The clear and definite example of other of narcotic analgesics for example comprises: acetyl fen (acetorphine); the acetyl group paracodin; Acetylmethadol (acetylmethadol); allyl kip Lip river fixed (allylprodine); α-Acetylmethadol (alphracetylmethadol); α-Meptin (alphameprodine); α-2-dimethylamino-4,4-diphenyl-5-heptanol (alphamethadol); benzene plug fixed (benzethidine); the benzyl morphine; Betacetylmethadol (betacetylmethadol); β-Meptin (betameprodine); β-2-dimethylamino-4,4-diphenyl-5-heptanol (betamethadol); β-Pu Luoding (betaprodine); Ke Nixin (clonitazene); the codeine MB; codeine N-oxide; uncommon general morphine (cyprenorphine); dihydrodesoxymorphine (desomorphine); dextrorotation is amide (dextromoramide) not; two general amide (diampromide); diethyl thiambutene (diethylthiambutene); paramorphane (dihydromorphine); two Meng Sai diindyls (dimenoxadol); diformazan enanthol (dimepheptanol); dimethyl thiambutene (dimethylthiamubutene); two
Phenanthrene is decided butyrate (dioxaphetyl butyrate); dipipanone (dipipanone); drotebanol (drotebanol); ethanol; ethyl-methyl thiambutene (ethylmethylthiambutene); rely on clatter suffering (etonitazene); rely on fragrant (etorphine); etoxeridine (etoxeridine); husband specific (furethidine); hydrogenation morphine alcohol (hydromorphinol); hydroxyl fixed generally (hydroxypethidine); ketone group shellfish rice ketone (ketobemidone); left-handed not amide (levomoramide); left-handed phenol acyl group mutter (levophenacylmorphan); methyl desoxymorphine (methyldesorphine); Methyldihydromorphine; morphine pyridine (morpheridine); morphine; the general amide of methyl (methylpromide); the morphine methanesulfonate ester; morphine-N-oxide; cough up fen (myrophin); naloxone (naloxone); naltrexone (naltyhexone); cigarette codeine (nicocodeine); cigarette morphine (nicomorphine); demethyl acyl group 2-dimethylamino-4,4-diphenyl-5-heptanol (noracymethadol); demethyl levo-dromoran (norlevorphanol); demethyl methadone (normethadone); the demethyl morphine; the demethyl ratio ketone (norpipanone) of muttering; his rope click of benzene is because of (pentazocaine); fen diindyl loose (phenadoxone); phenol is pacified general amide (phenampromide); phenol mutter (phenomorphan); the general pyridine of phenol (phenoperidine); his amide (piritramide) of pyrroles; pholcodine (pholcodine); general Suo Xin in heptan (proheptazoine); properdin (properidine); disopyramide (propiran); racemization is amide (racemoramide) not; Thebacon (thebacon); salt and hydrate that front three Puding (trimeperidine) is pharmaceutically acceptable with it.
Other clear and definite representative analgesic for example comprises: Acetaminophen (paracetamol); Aspirin and other are as above-mentioned NSAID; The NR2B antagonist; The bradykinin antagonist; The migraine agent; Anticonvulsants is as: Ou Kaisaiping (oxcarbazepine) and click fiber crops match flat (carmazepine); Antidepressant (as: TCA, SSRI, SNRI, P substance antagonist, or the like); The vertebra blocker; Jia Baoting (gabapentin); The asthma therapeutic agent, as: θ
2-adrenal gland swashs the property led receptor agonists; Leukotriene D
4Antagonist (for example: Meng Telike (montelukast);
Nx with
(all from pharmaceutical factory, Windsor (Sanofi WinthropPharmaceuticals; New York, NY)); LEVO-
(Reckitt﹠amp; The Coleman pharmaceutical factory; Richmond, VA);
(Purdue Pharma L.P. pharmaceutical factory; Norwalk, CT);
(Knoll pharmaceutical factory; Mount Olive, NJ);
(Janssen pharmaceutical factory; Titusville, NJ);
(all from the Endo pharmaceutical factory; Chadds Ford, PA);
IR, MS/S and MS/L are (all from the Richwood pharmaceutical factory; Florence, KY),
SR with
(all from Roxanne Laboratories laboratory; Columbus OH) reaches
(Bristol-Myers Squibb pharmaceutical factory; New York, NY).Other analgesic comprises the CB2-receptor agonists, as: AM1241, and the chemical compound that combines with α 2 delta-subunits, as: Ni Keding (Neurontin (Gabapentin)) and Pu Jialing (pregabalin).
In the others, this paper provide the VR1 regulator can with one or more LTRA (for example: suppress cysteamine acyl group leukotriene CysLT
1The medicament of receptor) is used in combination.CysLT
1Antagonist comprise Meng Telike (Montelukast) (
Merck﹠amp; Co.Inc.).These combinations can be used for treating pulmonary disease, as: asthma.
When treatment or prevention cough, the VR1 regulator that this paper provided can use with other drug regimen that is designed for this disease, as: antibiotic, antiinflammatory, cystamine anilide leukotriene, histamine antagonist, corticosteroid, class opiate, nmda antagonist, proton group Pu inhibitor, Nuo Saiping (nociceptin), neurokinin (NK1, NK2 and NK3) and bradykinin (BK1 and BK2) receptor antagonist, class cannabinol, Na+ dependency channel and large-scale conduction Ca
+ 2-dependency K
+-channel activator.Clear and definite medicament comprises that dexbrompheniramine (dexbrompheniramine) adds isoephedrine, Luo Dading (loratadine), American-European neat spirit (oxymetazoline), presses down general (ipratropium), A Buteluo (albuterol), Bake U.S. pine (beclomethasone), morphine, codeine, the pholcodine (pholcodeine) and dromethan (dextromethorphan) of putting down.
The present invention also provides the coupling therapy of treatment urinary incontinence.In this respect, the VR1 regulator that this paper provided can be designed for the drug regimen for the treatment of these diseases with other and use, as: controversies in hormone replacement in the elderly, Progesterone homologue, Vladimirovich Terekhin, Anatoli Leontievich, calcium channel blocker, Anticonvulsants, choline swashs the property led antagonist, anti-muscarine medicine, the plain antidepressant of three rings, SNRIs, Beta-adrenoreceptor agonist, phosphodiesterase inhibitor, potassium channel opener, Nuo Saiping (nociceptin)/Ou Fenni (orphanin) FQ (OP4) agonist, neurokinin (NK1 and NK2) antagonist, the P2X3 antagonist, myotrophy medicine and rumpbone neuroregulator.Clear and definite medicament comprises Ou Biting (oxybutinin), press down Puning (emepronium), Te Luoding (tolterodine), Fu Wasai (flavoxate), fluorine must fragrant (flurbiprofen), Te Luoding (tolterodine), two cyclammonium (dicyclomine), Pu Feiling (propiverine), Pu Sailing (propantheline), two cyclammonium (dicyclomine), press down general amine (imipramine), De Saiping (doxepin), De Leting (duloxetine), 1-removes amido-8-D-spermine acid angiotonin, muscarinic receptor antagonists, as: Te Luoding (Tolterodine) (
Pharmacia Corporation pharmaceutical factory) swash the property led agent with cholinolytic, as: Ou Biting (oxybutynin) (
Ortho-McNeil Pharmaceutical, Inc.Raritan, NJ).
VR1 regulator dosage suitable in these coupling therapies is usually as above-mentioned.Other removes the medical dosage of pain and medication administration method can be referring to for example: the explanation of manufacturer in Physician ' s DeskReference.In some specific embodiment, the VR1 regulator and one or more other remove the medicine of pain combination dispensing result required each therapeutic when making the generation medical effect the dosage reduction (for example: wherein the dosage of one or both medicaments can less than above-mentioned or maximum dose level that manufacturer advises 3/4, less than 1/2, less than 1/4 or less than 10%).
When being used for combination treatment, can comprise one or more again as above-mentioned other medicament as above-mentioned medical composition.In some these compositions, other medicament is an analgesic.The present invention also provides a kind of pharmaceutical preparation of packing, and it (for example: analgesic) comprises one or more VR1 regulators and one or more other medicaments in same packing.The pharmaceutical preparation of these packings generally includes: the container that (i) holds the medical composition that comprises the illustrated at least a VR1 regulator of this paper; (i) hold comprise as the container of the medical composition of above-mentioned at least a other medicament (as: medicament of alleviating pain and antiinflammatory) and (iii) indication how simultaneously, separate or use these combination treatments in regular turn or prevent the description (as: label or package insert) of the disease (as: disease that pain and inflammation occur) that the patient responds to the VR1 regulating action.
Chemical compound as the VR1 agonist for example also can be used on: colony control (substituting tear gas) or individual's protection (for example: be spray formula) or via the capsaicin receptor desensibilization, as treatment pain, scratch where it itches, the therapeutic of urinary incontinence or overactive bladder.Usually, be used for the series of compounds of colony's control or individual's protection according to known tear gas or allotment of pepper spray technology and use.
On the other hand, the non-medicine that the invention provides chemical compound that multiple this paper provides in vitro with purposes in vivo.For example: these chemical compounds are labelling in addition, (in as: cell preparation or tissue slice, preparation or its partly in) with being detecting and the probe of locating capsaicin receptor.In addition, this paper provides the chemical compound that comprises suitable reactions base (as: aryl, carbonyl, nitro or the nitrilo that changes) to can be used for the photoaffinity mark test of receptors bind position.In addition, chemical compound that this paper provides also is available as receptor active analytical test the yang aspect of yang matched group, as the reference material of the ability that combine with capsaicin receptor of decision candidate agent, or scan photography (PET) or single photon as the positron radial fault and radiate the photograph radiation tracer of (SPECT) of computer CT Scan.These methods can be used for describing the characteristic of capsaicin receptor in the live body.For example: the VR1 regulator can adopt multiple known techniques labelling (for example: radioactive label as the radionuclide of explanation herein as: tritium), with the one suitable period of sample constant temperature reaction (for example: analyze one section binding time decision earlier).After the constant temperature reaction, get rid of the not chemical compound of combination (for example: via washing), the chemical compound of combination has been (for example: automatic radiography or scintillation counting technique, the chemical compound of mensuration labelling radioactivity to adopt any suitable method detection of adopting label; The spectroscopic analysis test can be used for detecting cold light group and fluorescent group).Handling the paired sample contain the unmarked chemical compound of underlined chemical compound and higher amount (for example: surpass more than 10 times) according to same way as organizes in contrast.When the residual label content that detects is higher than matched group in the test sample, contain capsaicin receptor in the expression sample.Check and analysis tests (the automatic radiography of receptor (autoradiography) (receptor profile analysis of spectrum) that comprises capsaicin receptor in cultured cell or the tissue samples) can be set forth in Current Protocols in Pharmacology (1998) John Wiley﹠amp according to Kuhar; Sons, NewYork " in method in 8.1.1 to the 8.1.9. joint carry out.
The chemical compound that this paper provided also can be used for multiple known cytopheresis.For example: but surface within regulator connecting tissue culture plate or other carrier, with being the affinity ligand, with single from it (for example: single) from the cell that shows receptor in capsaicin receptor is fixed.In the preferred embodiment, regulator system links the fluorescent labelling thing, as luciferin, after cells contacting, uses fluorescent active cell sorter (FACS) analysis (or single from).
This paper provides the VR1 regulator can be further used for identifying other analytical test in conjunction with the preparation of capsaicin receptor.Generally speaking, these analytical tests are the test of standard competition binding analysis, wherein replace with test compound in conjunction with it underlined VR1 regulator warp.In brief, the mode of carrying out these analytical tests is: (a) by the chemical compound of capsaicin receptor and the illustrated underlined radioactivity of this paper, contact under the condition that can make chemical compound and capsaicin receptor combination, use generation in conjunction with it underlined chemical compound; (b) there be the detection signal corresponding down in no test preparation with combining it underlined compounds content; (c) by contacting with test preparation in conjunction with it underlined chemical compound; (d) in the presence of test preparation, detect the signal corresponding with combining it underlined compounds content; And the signal that (e) is detected with step (b) relatively, the signal of determination step (d) reduction degree.
Following example is for explanation usefulness, is not limited.Except as otherwise noted, otherwise all reagent and solvent are the standard merchandise level, are not further purified promptly to use again.Adopt customary modification method can change the step that starting material and other adopt, to make other chemical compound that this paper is provided.
Example
The mass spectrometric data of this example and following example is that EFI spills MS, system is according to the awl voltage (cone voltage) of cation mode with 15V or 30V, adopt instrument Micromass Time-of-FlightLCT (Micromass, Beverly MA), be equipped with Waters 600 and help the Pu, Waters 996 light two utmost points are arranged detector, and Gilson 215 Autosamplers and Gilson 841 micro-syringe are measured.Adopt MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) 4.0 editions softwares.Sample volume 1 microlitre is injected to 50 * 4.6mm ChromolithSpeedROD C18 tubing string, uses 2-phase linear gradient, flow velocity 6 ml/min molten from.Sample is measured total absorbance in 220-340nm UV scope.Moltenly be: mobile phase A-95/5/0.05 water/MeOH/TFA from condition; Mobile phase B-5/95/0.025 water/MeOH/TFA.
Gradient:
Time (minute) %B
0 10
0.5 100
1.2 100
1.21 10
Circulation is 2 minutes between the per injection.
Example 1
Be substituted the preparation of pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog
This example illustrates the method for making of representative intermediate product.
A.1-[4-(trifluoromethyl) pyridazine-3-yl] ethyl ketone
Will 3-chloro-4-(trifluoromethyl) pyridazine (200mg, 1.10mmol in sealed tube; Roughly as preparation as described at PCT International Publication No. WO2004/074290) (437mg 1.21mmol) is dissolved in the dry toluene (5mL) with tributyl (1-ethyoxyl-vinyl) stannum.This solution was led to argon 5 minutes with the argon balloon.Add Pd (PPh
3)
4(25.4mg, 0.022mmol) also that this mixture is overnight 110 ℃ of heating.This mixture is cooled to room temperature also to be filtered by diatomaceous earth (Celite) and washs with EtOAc.Solvent evaporates also should residual matter be dissolved among THF (10mL) and the 3NHCl (10mL).Stirred at room temperature 3 hours.Add EtOAc (100mL) and with H
2O (50mL), 1NNaOH (50mL) and saline (50mL) extraction.With this organic extract with Na
2SO
4Dry also with it volatilization.This crude product at the enterprising circumstances in which people get things ready for a trip layer analysis of silica gel, is at first dashed to carry then dashing with hexane/EtOAc (3: 1) with hexane and carries and must this title compound.LC/MS(MH
+)191.41。
B.2,2-two bromo-1-[4-(trifluoromethyl) pyridazine-3-yls] ethyl ketone
Will 1-[4-(trifluoromethyl) pyridazine-3-yl] (200mg 1.08mmol) is dissolved in the glacial acetic acid (5mL).Adding bromine also heats this solution 3 hours at 60 ℃.Cooling and volatilization.Add toluene (25mL) and volatilize twice and must this title compound.LC/MS(MH
+)346.96。
C.6-ethyoxyl-5-(trifluoromethyl) pyridine-2-amine
1.N-dibenzyl-6-ethyoxyl-5-(trifluoromethyl) pyridine-2-amine
Will N, N-dibenzyl-6-chloro-5-(trifluoromethyl) pyridine-2-amine (2.00g, 5.31mmol; Roughly as Horikawa et al. (2001) S.Chem.Pharm.Bull 49 (12): preparation as described in the 1621-27) be dissolved among the THF (100mL) and be cooled to 0 ℃.Drip NaOEt (2.68M is in EtOH for 5.93mL, 15.9mmol) to this mixture.After 30 minutes, heat this mixture to backwash and stirred 2 days.Removing this solvent also should residual matter be dissolved in EtOAc (100mL) and the water (100mL).Extract this water layer (2 * 100mL) with EtOAc.With this organic extract merging and with Na
2SO
4Dry.Under reduced pressure with this solvent removal.Should thick residual matter at the enterprising circumstances in which people get things ready for a trip layer analysis of silica gel, dash with hexane/EtOAc (9: 1) and to carry and must this title compound.LC/MS(MH
+)387.14。
2.6-ethyoxyl-5-(trifluoromethyl) pyridine-2-amine
Will N, (770mg 1.99mmol) is dissolved in the solution of MeOH (40mL) and AcOH (5mL) N-dibenzyl-6-ethyoxyl-5-(trifluoromethyl) pyridine-2-amine.Add 10%Pd (OH)
2/ C (140mg) is to this solution and with 50psi hydrogenation 7 hours.This catalyst of filtering is also with this solution concentration.Should residual matter be dissolved in EtOAc (100mL) and full closing in the NaHCO3 aqueous solution (100mL).With EtOAc extraction (2 * 100mL).With this organic extract merging and with Na
2SO
4Dry and must this title compound.
D.1-[2-methoxyl group-5-(trifluoromethyl) pyrimidine-4-yl] ethyl ketone
1.4-chloro-2-methoxyl group-5-(trifluoromethyl) pyrimidine
Will 2, and (6.54g 30.1mmol) is dissolved among the MeOH (50mL) 4-two chloro-5-(trifluoromethyl) pyrimidines.Add triethylamine (4.20mL, 30.1mmol) and overnight in stirring at room.Under reduced pressure remove this solvent.Should residual matter be dissolved in CH
2Cl
2(100mL) close in the NaHCO3 aqueous solution (100mL) with full.With CH
2Cl
2Extract this water (2 * 100mL).Merging, dry and this organic extract that volatilizees.With this crude product at the enterprising circumstances in which people get things ready for a trip layer analysis of silica gel, with hexane/Et
2O (97: 3) gets two kinds of structural isomerism things towards carrying, and this title compound has bigger polarity.LC/MS(MH
+)213.13。
2.1-[2-methoxyl group-5-(trifluoromethyl) pyrimidine-4-yl] ethyl ketone
(590mg, 2.77mmol) (1.10mg 3.05mmol) is dissolved in the dry toluene (7mL) Will 4-chloro-3-methoxyl group-5-(trifluoromethyl) pyrimidine in sealed tube with tributyl (1-ethyoxyl-vinyl) stannum.This solution was led to argon 5 minutes with the argon balloon.Add Pd (PPh
3)
4(64mg, 0.055mmol) also that this mixture is overnight 110 ℃ of heating.This mixture is cooled to room temperature also to be filtered by diatomaceous earth (Celite) and washs with EtOAc.Solvent evaporates also should residual matter be dissolved among THF (30mL) and the 2N HCl (30mL).Stirred overnight at room temperature.With this mixture with ice bath cooling and with the NaOH alkalization of 6N.With EtOAc (2 * 100mL) extractions.With this organic extract merging and with H
2O (50mL), 1N NaOH (50mL) and saline (50mL) extraction.With this organic extract with Na
2SO
4Dry also with it volatilization.Should thick residual matter at the enterprising circumstances in which people get things ready for a trip layer analysis of silica gel, at first dash to carry then dashing and carry and must this title compound with hexane/EtOAc (3: 1) with hexane.LC/MS(MH
+)221.06。
Example 2
Other representativeness be substituted pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog it
Synthetic
A.N-[5-(trifluoromethyl) pyridine-2-yl]-7-[4-(trifluoromethyl) pyridazine-3-yl]-1,8-naphthyridines-4-amine (chemical compound 1)
(1.6g 6.2mmol) is dissolved in anhydrous CH with 4-chloro-3-formoxyl pyridine-2-aminocarbamic acid tributyl under nitrogen atmosphere
2Cl
2(50mL).(2.4M1 is 31.0mmol) to this reactant mixture and overnight in the room temperature heating to drip trifluoro formic acid.Add saturated aqueous sodium carbonate (50mL) to this reactant mixture, this organic layer is separated, with CH
2Cl
2Aqueous phase extracted layer (2 * 20mL) and with MgSO
4Dry.Under reduced pressure filter and concentrate and must be the title product of yellow solid.
2.5-chloro-2-[4-(trifluoromethyl) pyridazine-3-yl]-1, the 8-naphthyridines
Will 1-[4-(trifluoromethyl) pyridazine-3-yl] (105mg, 0.552mmol) (86mg 0.552mmol) is dissolved among the anhydrous THF (10mL) ethyl ketone with 2-amino-4-chlorine cigarette aldehyde.With this mixture be cooled to-30 ℃ and with gradation during 30 minutes add KtBuO (124mg, 1.10mmol).This mixture was stirred 30 minutes again again.Under reduced pressure remove this solvent (heating does not proceed to bone dry).Add ice (20g) and saturated NH
4Cl aqueous solution (20mL).The solid that filtering produced (product) and with cold water washing.With precipitate dry (60 ℃) 2 hours and must this title compound in vacuum drying oven.LC/MS(MH
+)311.01。
(3.N-[5-trifluoromethyl) pyridine-2-yl]-7-[4-(trifluoromethyl) pyridazine-3-yl]-1,8-naphthyridines-4-amine (chemical compound 1)
Will 5-chloro-2-[4-(trifluoromethyl) pyridazine-3-yl in sealed tube]-1, the 8-naphthyridines (115mg, 0.370mmol), 2-amino-5-trifluoromethyl-pyridine (75mg, 0.463mmol) and Cs
2CO
3(398mg 1.22mmol) is dissolved in two oxa-s, six rings (5mL).This solution was led to argon 5 minutes with the argon balloon.Add Pd
2Dba
3(PPh
3)
4(34mg, 0.037mmol) and with xanpthos (22mg 0.037mmol) and with this solution led to argon 5 minutes with the argon balloon.Seal this pipe and overnight 110 ℃ of heating.Cool off this mixture and filter this solution by diatomaceous earth with the ethyl acetate dilution.Under reduced pressure concentrate this and leach thing.With this thick residual matter of PTLC purification with CH
2Cl
2/ MeOH/NH
4OH (95/5/1) dashes and to carry and must this title compound.1H?NMR(CDCl
3)δ9.54(d，1H)，9.07(br，s，1H)，8.71(d，1H)，8.64(s，1H)，8.20(d，1H)，8.8(br?m，2H)，7.96(d，1H)，7.89(d，1H)，7.25(d，1H).LC/MS(MH
+)436.09。The analytical test that this IC50 value is provided in embodiment 6 is less than 1 micromole.
B.N-[5-(trifluoromethyl) pyridine-2-yl]-3-[4-(trifluoromethyl) pyridin-3-yl] pyrido [2,3-B] pyridazine-8-amine (chemical compound 2)
(1.3-[4-trifluoromethyl) pyridazine-3-yl] pyrido [2,3-b] pyridazine-8-amine
With 2,2-two bromo-1[4-(trifluoromethyl) pyridazine-3-yls] ethyl ketone (375mg, 0.463mmol), pyridine-2,3,4-triamine dihydrobromide (228mg, 1.19mmol, roughly as preparation as described in Kogl et al. (1948) the Recueil des Travaux Chimiques des Pays-Baset de la Beligique 67:29-44) and NaHCO3 (726mg 8.64mmol) is dissolved in H
2O (10mL) and two allows assorted six alkane (5mL).100 ℃ of heating 3 hours.The cooling and with EtOAc (3 * 50mL) extraction.Merge this organic extract and with saline (100mL) extraction with Na
2SO
4Dry.This solvent under reduced pressure volatilizees.With this thick residual matter of PTLC purification with CH
2Cl
2/ MeOH/NH
4OH (90/10/1) dash carry and 2: 1 mixture of two kinds of different structure isomeric compounds, wherein this title compound is for mainly than the polar peer of tool.
LC/MS(MH
+)293.11。
(2.N-[5-trifluoromethyl) pyridine-2-yl]-3-[4-(trifluoromethyl) pyridazine-3-yl] pyrido [2,3-b] pyrazine-8-amine (chemical compound 2)
Will 3-[4-(trifluoromethyl) pyridazine-3-yl in sealed tube] pyrido [2,3-b] pyrazine-8-amine (38mg, 0.129mmol), 2-chloro-5-trifluoromethyl-pyridine (24mg, 0.129mmol) and Cs
2CO
3(126mg 0.387mmol) is dissolved in anhydrous two oxa-s, six rings (5mL).This solution was led to argon 5 minutes with the argon balloon.Seal this pipe and overnight 110 ℃ of heating.Cooling off this mixture dilutes to room temperature and with EtOAc (10mL).Filter this solution and wash by diatomaceous earth with EtOAc.This solvent under reduced pressure volatilizees.With this thick residual matter of PTLC purification with CH
2Cl
2/ MeOH/NH
4OH (95/5/1) dashes and to carry and must this title compound.1H?NMR(CDCl
3)δ9.59(d，1H)，9.56(s，1H)，9.54(br，s，1H)，9.13(d，1H)，8.99(d，1H)，8.73(br，s，1H)，8.01(d，1H)，7.92(dd，1H)，7.22(d，1H).LC/MS(MH
+)437.08。This IC
50The analytical test that value is provided in embodiment 6 is less than 1 micromole.
C.5-(trifluoromethyl)-4-(5-{[5-(trifluoromethyl) pyridine-2-yl] amino-1,8-naphthyridines-2-yl) pyrimidine-2-phenol (chemical compound 3)
(1.4-5-chloro-1,8-naphthyridines-2-yl)-5-(trifluoromethyl) pyrimidine-2-phenol
Will 1-[2-methoxyl group-5-(trifluoromethyl) pyrimidine-4-yl] (211mg, 0.958mmol) (150mg 0.958mmol) is dissolved among the anhydrous THF (15mL) ethyl ketone with 2-amino-4-chlorine cigarette aldehyde.With this mixture be cooled to-30 ℃ and with gradation during 30 minutes add KtBuO (215mg, 1.92mmol).This mixture was stirred 30 minutes again again.Under reduced pressure remove this solvent (heating does not proceed to bone dry).Add ice (20g) and saturated NH
4Cl aqueous solution (20mL).The solid that filtering produced and with cold water washing.Precipitate dry (85 ℃) in vacuum drying oven is overnight and must this title compound.LC/MS(MH
+)327.11。
(2.5-trifluoromethyl)-4-(5-{[5-(trifluoromethyl) pyridine-2-yl] amino }-1,8-naphthyridines-2-yl) pyrimidine-2-phenol
Will 4-in sealed tube (5-chloro-1,8-naphthyridines-2-yl)-5-(trifluoromethyl) pyrimidine-2-phenol (237mg, 0.725mmol), 2-amino-5-trifluoromethyl-pyridine (176mg, 1.09mmol) and Cs
2CO
3(709mg 2.18mmol) is dissolved in anhydrous two oxa-s, six rings (7mL).This solution was led to argon 5 minutes with the argon balloon.Add Pd
2Dba
3(PPh
3)
4(66mg, 0.0725mmol) and xanpthos (42mg, 0.0725mmol) and with this solution with the logical argon of argon balloon 5 minutes.Seal this pipe and overnight 110 ℃ of heating.Cool off this mixture and with Et
2The O dilution.Filter this solution by diatomaceous earth.Abandon this and leach thing.Wash this diatomaceous earth bed with MeOH.Under reduced pressure concentrate this and leach thing.With this thick residual matter of silica gel purification with CH
2Cl
2/ MeOH (90/10) dashes and to carry and must this title compound.LC/MS(MH
+)453.10。
D.7-[2-chloro-5-(trifluoromethyl) pyrimidine-4-yl]-N-[5-(trifluoromethyl) pyridine-2-yl]-1,8-naphthyridines-4-amine (chemical compound 4)
With 5-(trifluoromethyl)-4-(5-{[5-(trifluoromethyl) pyridine-2-yl] amino-1,8-naphthyridines-2-yl) (45mg 0.106mmol) is dissolved in POCl to pyrimidine-2-phenol
3Also the backwash heating is overnight (10mL).Cooling also under reduced pressure removes excessive POCl
3Should be residual be dissolved in EtOAc (100mL) and saturated NaHCO
3In the aqueous solution (100mL).Extract this water (3 * 50mL) with EtOAc.Merging, drying are also volatilized this organic extract and are got title compound.LC/MS(MH
+)471.04。
E.N-[5-(trifluoromethyl) pyridine-2-yl]-7-[5-(trifluoromethyl) pyridin-4-yl]-1,8-naphthyridines-4-amine (chemical compound 5)
With 7-[2-chloro-5-(trifluoromethyl) pyrimidine-4-yl]-N-[5-(trifluoromethyl) pyridine-2-yl]-1, (45mg 0.096mmol) is dissolved in M to 8-naphthyridines-4-amine
EAmong the OH (10mL).Add HCO
2NH
4(70mg, 1.10mmol) and Pd/C (15mg).Stirred 6 hours stirring at room 1 hour and at 60 ℃.Cooling is also filtered by diatomaceous earth, washs this diatomaceous earth bed with MeOH.Under reduced pressure concentrate this solution.Must this title compound with this crude product of PITC purification.1H?NMR(CD
3OD)δ9.53(s，1H)，9.35(s，1H)，9.09(d，1H)，8.94(d，1H)，8.67(d，1H)，8.51(br，s，1H)，8.09(d，1H)，8.02(dd，1H)，7.42(d，1H).LC/MS(MH
+)437.00。This IC
50The analytical test that value is provided in embodiment 6 is less than 1 micromole.
Example 3
Other representativeness is substituted pyridazinyl-quinolyl-4 amine and pyrimidine-quinolyl-4 amine analog
Adopt customary modification method, change starting material, and adopt other step, can produce other chemical compound that this paper provides.For example, use and describe As N-[5-(trifluoromethyl) pyridine-2-yl]-7-[4-(trifluoromethyl) pyridazine-3-yl]-1,8-naphthyridines-4-amine and 6-ethyoxyl-5-(trifluoromethyl) pyridine-2-amine replaced with 2-amino-5-trifluoromethyl-pyridine produce N-[6-ethyoxyl-5-(trifluoromethyl) pyridine-2-yl]-7-[4-(trifluoromethyl) pyridazine-3-yl]-1,8-naphthyridines-4-amine (chemical compound 5).
Chemical compound shown in Table I and the II is to adopt these method preparations.Chemical compound shown in the Table I is IC in the analysis Try Examination that example 6 is provided
50Value is 1 little not ear concentration or following.LC/MS Number According represents with M+1.In Table III, " IC
50" in the hurdle " * " representative, the IC of the analytical test that is provided at example 6
50Value is a not ear of following 1 milli.
Table I
Table II
Table III
Example 4
VR1-transfectional cell and film preparation
This example explanation is used for the VR1-transfectional cell and the method for making that contains the film preparation of VR1 of capsaicin binding analysis test (example 5).
Get complementary deoxyribonucleic (cDNA) (the United States Patent (USP) case No.6 of human capsaicin receptor total length coding, 482,611 SEQ ID NO:1,2 or 3) inferior choosing is grown (subclone) to plastid pBK-CMV (Stratagene, La Jolla, CA), for reorganization performance in mammalian cell.
With standard method, the human capsaicin receptor total length of transfection pBK-CMV coding performance structure is to human embryo kidney dirty (HEK293) cell.Cultivated for two weeks in the culture medium of the cell of transfection through containing G418 (400 μ g/ml) to choose, obtain the cell of a group stable transfection.Via limit number dilution method, list obtains the stable cell strain of pure lines from going out independent pure lines in group's cell since then, uses for next test.
When carrying out the test of radioactivity ligand associativity, inoculating cell does not contain in the culture medium of antibiotic to the T175 Tissue Culture Flask, grows to about 90% dishful.Culture bottle is with after PBS washing, collecting cell in the PBS that contains 5mM EDTA.Cell is kept under-80 ℃ through the centrifugal assembly in bulk of gentleness, till analyzing.
Previous freezing cell is placed ice-cold hydroxyethyl piperazine ethanesulfonic acid (HEPES) homogenizing buffer (5mM KCl, 5.8mM NaCl, 0.75mM CaCl
2, 2mM MgCl, 320mM sucrose and 10mMHEPES pH 7.4) in to organize homogenizer to break.Organize homogenizing fluid prior to following centrifugal 10 minutes of 1000xg (4 ℃), to remove nucleus partly and cell debris, get for the first time centrifugal upper clear liquid then again in 35,000xg (4 ℃) centrifugal 30 minutes down obtains partly membranous part part of purification.Film elder generation resuspending is just analyzed after in HEPES homogenizing buffering.Get a film homogenizing fluid, utilize Bradford method (BIO-RAD protein analysis cover group, #500-0001, BIO-RAD, Hercules, CA) mensuration protein concentration.
Example 5
The test of capsaicin receptor binding analysis
The representative analytical test of this example explanation capsaicin receptor associativity, it can be used for measuring the binding affinity of chemical compound to capsaicin (VR1) receptor.
With [
3H] resin toxin (resiniferatoxin) associativity test (RTX) is to carry out according to the method that illustrates among Szallasi and Blumberg (1992) J.Pharmacol.Exp.Ter.262:883-888 basically.In the method, non-specificity RTX associativity can be added cattle α after finishing when association reaction
1Acid glucoprotein (every arm 100 micrograms) and descending.
[
3H] RTX (37Ci/ milli not ear) is chemosynthesis and (the Chemical Synthesis andAnalysis Laboratory of assay laboratory by National Cancer Institute-Fei Delike cancer research and centre of development, National Cancer Institute-Frederick CancerResearch and Development Center, Frederick MD) is synthesized into.[
3H] but RTX also the self-sales merchant and get (for example: pharmaceutical factory Amersham Pharmacia Biotech, Inc.Piscataway, NJ).
The film homogenizing fluid for the treatment of excess syndrome example 4 in the homogenizing buffer, reaches protein concentration 333 μ g/ml according to above-mentioned centrifugal and resuspending.Prepare the affinity analysis test mixture on ice, wherein comprise [
3H] RTX (specific activity 2200mCi/ml), 2 μ l non-radioactive activity test chemical compounds, 0.25mg/ml bovine serum albumin (Cohn is V partly), with 5 * 10
4To 1 * 10
5The VR1-transfectional cell.Use above-mentioned ice-cold HEPES homogenizing buffer (pH 7.4) to adjust final volume to 500 μ l (being used for the test of state of conflict binding analysis) or 1,000 μ l (being used for the test of saturation type binding analysis).Non-single-minded associativity be defined as the active RTX of 1 μ M non-radioactive (Alexis Corp.San Diego, CA) have a purgation associativity.When analyzing saturated associativity, [
3H] the interpolation concentration range of RTX is 7 to 1,000pM dilutes 1 to 2 time.Typical case's practice is that every saturated associativity curve is collected 11 concentration point.
The test of state of conflict binding analysis lies in 60pM[
3H] carry out under the existence of test compound of RTX and variable concentrations.Mat moves to analysis of mixtures in 37 ℃ of water-baths, initial associativity reaction, and the constant temperature reaction placed cooled on ice with test tube, with stopped reaction after 60 minutes.With the WALLA glass fiber filter paper filter (PERKIN-ELMER, Gaithersburg MD) (soaked 1.0%PEI (polymine) 2 hours earlier before using), the RTX of film combination by this with the RTX and any and α that dissociate
1The RTX of acid glucoprotein combination separates.Make filter paper after the dry night, add WALLAC BETASCINT scinticounting liquid, on WALLAC 1205BETA PLATE enumerator, count.
Balance is in conjunction with the numerical value substitution allostery Xi Er formula (theallosteric Hill equation) of system of parameters with gained, mat computer program FITP (Biosoft, Ferguson MO) judges (being illustrated in they (1993) of people J.Pharmacol.Exp.Ther.266:678-683 such as Szallasi) calculating data.Chemical compound that this paper provides in this analytical test to the K of capsaicin receptor
iValue is less than 1 μ M, 100nM, 50nM, 25nM, 10nM or 1nM.
Example 6
Calcium moves analytical test
The explanation of this example is used for the representative calcium mobile analytical test of the agonist and the antagonist activities of analytical test chemical compound.
Through the performance plastid transfection (described) according to example 4 use the performance human capsaicin receptor cell inoculation to the FALCON black surround, (Franklin Lakes NJ), grows to 70 to 90% dishfuls for #3904, BECTON-DICKINSON in 96 porose discs of dianegative.Turn culture medium in 96 porose discs, in each hole, add FLUO-3AM calcium sensitivity dyestuff (Molecular Probes, Eugene, OR) (dye solution: the DMSO solution of 1 milligram of FLUO-3 AM, 440 μ L DMSO and 440 μ l, 20% general sieve nicotinic acid (pluronic acid), in Ke Shi-Lin Geshi (Krebs-Ringer) HEPES (KRH) buffer (25mM HEPES, 5mM KC1,0.96mM NaH
2PO
4, 1mM MgSO
4, 2mM CaCl
2, 5mM glucose, 1mM probenecid (probenecid), pH 7.4) in dilution 1: 250, every hole 50 μ l dilute solutions).Analysis disc covers with aluminium foil, in 37 ℃ the 5%CO that contains
2Environment was cultivated 1 to 2 hour down.After the cultivation, the dyestuff in the turned letter culture plate, with KRH buffer washed cell once, resuspending is in the KRH buffer.
Capsaicin EC
50Algoscopy
Show the ability to promoting or picking the anticalcium mobile response in the cell for the determination test chemical compound is the capsaicin receptor of capsaicin or other class cephrol agonist, therefore measure the EC of agonist capsaicin earlier
50In each porocyte, add 20 μ l KRH buffer and 1 μ l DMSO according to above-mentioned preparation.Adopt the FLIPR instrument, add 100 μ l automatically and contain the KRH buffer of capsaicin to each hole.Adopt fluorescent scanner (FLUOROSKAN ASCENT) (Labsystems; Franklin, MA) or FLIPR (fluorescent analyzer showing board frame of reference; Molecular Devices, Sunnyvale, CA) the calcium migration that brings out of instrument monitoring capsaicin.Make the concentration-response curve of 8 points to use data between 30 to 60 seconds behind the agonist, final capsaicin concentration is 1nM to 3 μ M.Employing KALEIDAGRAPH software (Synergy Software, Reading, PA) with data substitution formula:
y＝a*(l/(l+(b/x)
c))
Excite concentration (excitatory concentration with 50% of assaying reaction; EC
50).In this formula, y is the highest fluorescent signal, and x is agonist or antagonist (referring to capsaicin at this moment) concentration, and a is E
MaxB is equivalent to EC
50Value, and c is hill coefficient (Hill coefficient).The judgement of agonist activity.
Get test compound and be dissolved among the DMSO, in the KRH buffer, dilute, add to immediately according in the cell of above-mentioned preparation.Also add 100nM capsaicin (about EC
90Concentration) cell to the identical 96 hole culture plates is as positive controls.The ultimate density of analyzing test compound in the hole is between 0.1nM to the 5 μ M.
The ability that test compound act as capsaicin receptor agonists depends on the fluorescent reaction of the cell of measuring the performance capsaicin receptor, and this fluorescent reaction system brings out and is the function with the compound concentration variation through chemical compound.Data according to the aforesaid way substitution, are obtained EC
50, the result less than 1 little not ear concentration, is preferably less than 100nM usually, is more preferred from less than 10nM.Also calculate the effectiveness degree of each test compound for the reaction of bringing out by the 100nM capsaicin by the reacting phase of specifying test compound concentration (being typically 1 μ M) to bring out.This numerical value is called signal percentage ratio (POS), is calculated by following formula:
The reaction of POS=100* test compound reaction/100nM capsaicin
This analytical test provides a kind of while analytical test chemical compound as the intensity of human capsaicin receptor agonist and the quantitative method of effectiveness.The agonist of human capsaicin receptor brings out the reaction that can detect usually under less than 100 μ M concentration, or is preferably the concentration less than 1 μ M, or the best is the concentration less than 10nM.It is preferably greater than 30 POS the effectiveness degree of human capsaicin receptor when 1 μ M concentration, is more preferred from greater than 80 POS.In the analytical test that some agonist illustrates hereinafter, under the compound concentration that is lower than 4nM, there is not the antagonist activities that can detect, confirm that promptly it does not have antagonist activities basically, be more preferred from the concentration that is lower than 10 μ M, and best for being less than or equal to the concentration of 100 μ M.
The antagonist activities algoscopy
Get test compound and be dissolved among the DMSO,, make and analyze that final test compound concentration is between 1 μ M to the 5 μ M in the hole, add in the cell as above-mentioned preparation with 20 μ l KRH buffer dilutions.Getting 96 porose discs that contain the cell for preparing and test compound cultivated 0.5 to 6 hour in dark with under the room temperature.It should be noted that incubation time is unsustainable surpasses 6 hours.Be about to measure before the fluorescent reaction, the side utilizes the automatic 100 μ l of interpolation of FLIPR instrument to contain in each hole of KRH buffer to 96 porose disc of capsaicin, and its concentration is as the above-mentioned EC that records
50Double strength, the final sample volume is 200 μ l, final capsaicin concentration equals EC
50The ultimate density of analyzing test compound in the hole is between 1 μ M to the 5 μ M.The antagonist of capsaicin receptor is preferably 1 little not ear concentration or following concentration in 10 little not ear concentration or following concentration, makes this reacting phase (that is under the existence of no test compound, use twice EC for the matched control group
50The cell of the Capsaicin Treatment of concentration) reduce at least about 20%, be preferably at least about 50%, the best is at least 80%.Get with respect in the presence of capsaicin and do not have that observed reaction of arriving reduces by 50% o'clock required antagonist concentration under the antagonist, be the IC of antagonist
50, be preferably and be lower than 1 little not ear concentration, 100 Nai Moer concentration, 10 Nai Moer concentration or 1 Nai Moer concentration.
Some preferable VR1 regulator is in above-mentioned analytical test, when under the compound concentration that is lower than 4nM, not having the agonist that can detect active, confirm that promptly it does not have the agonist activity basically, be more preferred from the concentration that is lower than 10 μ M, and best for being less than or equal to the concentration of 100 μ M.
Example 7
Microsome is the half-life in vitro
This embodiment illustrates and uses the assessment of representative liver microsomes half-life analytical test to chemical compound elimination half life values (t1/2 value).
(Kansas City KS) gets (pooled) people's who merges liver microsomes from XenoTech LLC.These liver microsomes also can from In Vitro Technologies (Baltimore, MD) or Tissue Transformation Technologies (Edison, NJ).Prepare six groups of test reactions, respectively comprise 25 l microsomes, (19 milliliters of 0.1M NaH2PO4,81 milliliters of 0.1M Na2HPO4 are with H for solution 5 l of 100M test compounds and 0.1M phosphate buffer
3PO
4Be adjusted to acid-base value 7.4) 399 l.The 7th prepared in reaction is as comprising the MC positive control group of 25 l, the 100M solution of the chemical compound of 0.1M phosphate buffer 399 l and the known metabolic of 5 l tools (for example, flat (DIAZEPAM) or clozapine (CLOZAPINE) of phenodiazine).React on 39 ℃ of pre-constant temperatures 10 minutes.
Cofactor mixture mat 16.2 milligrams of NADP of dilution and 45.4 milligrams of G-6-P salt prepare in 4 milliliters of 100mM magnesium chlorides.G-6-P salt dehydrogenase solution is by dilution 214.3 l G-6-P salt dehydrogenase suspending agent (Roche MolecularBiochemicals; Indianapolis IN) goes into the preparation of 1285.7 l distilled water.71 l initial action mixture (3 milliliters of cofactor mixture; 1.2 milliliter G-6-P salt dehydrogenase solution) add 5 and positive control group in 6 groups of test reactions.71 l 100mM magnesium chlorides add the 6th test reaction, use as the negative control group.In every time point (0,1,3,5 and 10 minutes), each reaction mixes 75 l and draws the hole that adding includes the ice-cold acetonitrile 96-of 75 l porose disc.Sample lies in 3500 rpms of whirlpools and stirs and centrifugal 10 minutes (SorvalT 6000D centrifuge, HlOOOB swiveling wheel).Move to each hole from the 75 l supernatantes of each reaction, it includes 0.5M solution 150 l of it (internal standard) chemical compound of known LCMS figure.The amount of carrying out the lcms analysis of each sample and measuring not metabolism test compounds is as area under curve (AUC), and compound concentration was mapped to the time, and outer t1/2 value of spreading to test compounds., show in vitro greater than 10 minutes and be less than 4 hours t1/2 value in people's liver microsomes in this preferable chemical compound that provides, preferable between 30 minutes and 1 hour.
Example 8
The test of MDCK oxicity analysis
This embodiment illustrates the assessment of the cytotoxicity analysis test of use Madin Darby dog kidney (MDCK) cell to toxicity of compound.
(CT) making the ultimate density of the chemical compound in the analytical test is 10 little not ears, 100 little not ears or 200 little not ears for PACKARD, Meriden in each hole of clear bottom 96-porose disc to add test compound 1 μ L.Add the solvent that does not contain test compound and organize the hole in control.
Mdck cell, (American Type CultureCollection, Manassas VA), are maintained at aseptic condition and follow in the ATCC product information and indicate ATCC number .CCL-34.The mdck cell of dishful is through trypsin hydrolyzing, collects and is diluted to density 0.1x10 with warm (37 ℃) culture fluid (VITACELL minimal essential medium (minimum essential medium) Eagle, ATCC make a catalogue #30-2003)
6Cells/ml.The cell 100 μ L of dilution add each hole, do not contain five standard curve control group holes of cell except containing the warm culture fluid of 100 μ L.Culture plate is in 37 ℃ of stable concussions 2 hours under 95%02,5% carbon dioxide then.After cultivating, add 50 μ L cells of mamma animals hydrating solutions (by PACKARDMeriden, CT) the luminous ATP of ATP-LITE-M measures the cover group) to each hole, scraps of paper blanketing is pasted with PACKARDTOPSEAL in the hole, changes concussion 2 minutes with suitable vibrator in about per minute 700.
With respect to undressed cell, the chemical compound of intoxicating will reduce ATP and produce.ATP-LITE-M cold light ATP measure the cover group generally according to manufacturer be illustrated in processing with undressed mdck cell in measure the generation of ATP.PACKARD ATP LITE-M reagent is allowed to balance to room temperature.In case balance is reformulated in 5.5 milliliters of substrate buffer solution (by the cover group) by freeze dried matrix solution.Freeze dried ATP standard solution reassembles into 10mM with the water of deionization and deposits product.Five control group holes, the PACKARD titer of 10 μ L serial dilutions is incorporated in each hole, and the ultimate density that obtains the serial dilution hole is 200nM, 100nM, 50nM, 25nM and 12.5nM.It is porose in institute to add PACKARD matrix solution (50 μ L), and blanketing changes concussion 2 minutes in suitable vibrator with about per minute 700 then then.White PACKARD pastes the scraps of paper and is attached at each tray bottom, and sample mat Aluminium Foil Package is coated with shading and placed dark 10 minutes.Use the cold light register in 22 ℃ of mensuration cold light (that is, the little dish flicker of PACKARD TOPCOUNT and cold light register or TECAN SPECTRAFLUOR PLUS) then, and ATP content is calculated by standard curve.The ATP content of compound treatment cell is through relatively judging with unprocessed cell after tested.Cell is handled system with preferable test compounds 10 μ M and is shown the ATP degree at least in 80%, and preferably at least 90%, undressed cell.When 100 μ M concentration of use test chemical compound, cell is handled system with preferable test compounds and is shown that at least the ATP degree in 50%, preferably detects ATP degree at least 80%, in undressed cell.
Example 9
The test of dorsal root ganglion cell analysis
This example explanation is used to assess the VR1 antagonist of chemical compound or the representative dorsal root ganglion cell analysis test of agonist activity.
According to standard method (Aguayo and White (1992) Brain Research 570:61-61), in newborn rat, downcut DRG, separate and cultivation.Cultivate after 48 hours, washed cell once, with calcium sensitivity dyestuff Fluo 4 AM (2.5 to 10 μ g/ml; TefLabs, Austin TX) cultivated 30 to 60 minutes.And then washed cell once.Adopt fluorometer to measure the variation of Fluo 4 fluorescents, follow the trail of intracellular calcium concentration because of adding capsaicin variation with the VR1 increase to the cell.Collect 60 to 180 seconds data, measure the highest fluorescent signal.
In the antagonist analytical test, the chemical compound that adds variable concentrations is to cell, is the function fluorescent signal curve that draws then with the compound concentration, reaches concentration required when suppressing 50% capsaicin priming reaction with differentiation, or IC
50The preferable IC of the antagonist of capsaicin receptor
50Be lower than 1 little not ear concentration, 100 Nai Moer concentration, 10 Nai Moer concentration or 1 Nai Moer concentration.In the agonist analytical test, the chemical compound that adds variable concentrations is to not adding in the cell of capsaicin.When following the trail of the variation of Fluo-4 fluorescent as the chemical compound employing fluorometer of capsaicin receptor agonists, intracellular calcium concentration can increase with VR1.The 50% o'clock desired concn that reaches the highest signal of capsaicin priming reaction is EC
50, it is preferably and is lower than 1 little not ear concentration, is lower than 100 Nai Moer concentration or is lower than 10 Nai Moer concentration.
Example 10
Judge the zootype of pain releasing
This example explanation analysis of compounds is removed the exemplary process of pain degree.
A. pain is removed test
Following method is to be used to analyze pain to remove degree.
The unusual pain of mechanicalness
Basically according to people such as Chaplan they (1994) J.Neurosci.Methods 53:55-63 and Tal and they (1998) of Eliav Pain 64 (3): the unusual pain of methods analyst mechanicalness (to the abnormal response of non noxious stimulation generation) that illustrates among the 511-518.Fan Furui (von Frey) silk thread (being typically a series of 8 to 14 kinds of silk threads) of getting a series of different-stiffness is applied on the rear foot plantar surface, and its strength just foot makes the silk thread bending.Silk thread keeps this position to be no more than for 3 seconds or till positive unusual pain reaction appears in big rat.Positive unusual pain reaction comprises the rear foot that lifts processing, licks immediately or shakes foot.Adopt the gloomy analytical test (Dixon up-downmethod) up and down of Dick to determine applying in proper order and frequency of each silk thread.Wait silk thread to begin test among using in this series, subsequently according to order continuous administration up or down, whether the silk thread that uses feminine gender or positive reaction occur and decides during respectively according to beginning.
If when the big rat of accepting these compound treatment need use Fan Furui (von Frey) silk thread of higher stiffness can cause positive unusual pain reaction compared to untreated control group or base processed group big rat, represent that this chemical compound can effectively reverse or prevent the symptom of the unusual pain of similar mechanicalness.Perhaps, or in addition, the chronic pain of test animal after can before chemical compound is given in throwing, reaching.In these analytical tests, required silk thread or unprocessed or handle and also have a required silk thread of animal of chronic pain through base when bringing out reaction before handling, active compound can make and bring out the required silk thread rigidity of reaction after the processing and improve.Test compound is offerd medicine before or after lying in the pain outbreak.When test compound is offerd medicine after the pain outbreak, test in dispensing and carried out in back 10 minutes to 3 hours.
Mechanical hyperalgesia
Basically according to they (1996) of people such as Koch Analgesia 2 (3): the method for 157-164 explanation is measured mechanical hyperalgesia (to the overresponse of pain stimulation).Get in indivedual cages that big rat placed warm porous metals floor.After gentle acupuncture on arbitrary the rear foot plantar surface, interval in the mensuration rear foot is drawn back (that is animal is put back to its rear foot the time of maintenance before on the floor).
If chemical compound make the rear foot draw back in interval shorten when reaching showing property of statistics, then this chemical compound can reduce mechanical hyperalgesia.Test compound is offerd medicine before or after lying in the pain outbreak.When test compound is offerd medicine after the pain outbreak, tested in back 10 minutes to 3 hours in dispensing.
Thermal hyperalgesia
Basically be illustrated in (1988) Pain.32 (1) according to people such as Hargreaves: method is measured thermal hyperalgesia (to the overresponse of harmful thermostimulation) among the 77-88.In brief, the plantar surface at arbitrary rear foot of animal applies constant radiant heat source.Draw back the time (that is animal is moved rear foot phase heat time heating time before) of the rear foot, or be called hot threshold value or incubation period, can determine the sensitivity of the animal rear foot heat.
If chemical compound make the rear foot draw back in interval add and reach statistics during showing property (that is extending hot threshold value or incubation period that reaction occurs), then this chemical compound can reduce thermal hyperalgesia.Test compound is offerd medicine before or after lying in the pain outbreak.When test compound is offerd medicine after the pain outbreak, after dispensing, tested 10 minutes to 3 hours.
B. pain pattern
Can adopt following any method to bring out pain, render a service with the pain relieving of measuring chemical compound.Generally speaking, when adopting male SD rat and following at least a pattern, chemical compound that this paper provides can make pain show on adding up in above-mentioned at least a test method(s) to reduce.
Acute inflammation pain pattern
Acute inflammation pain system is illustrated in (1997) Br.J.Pharmacol.121 (8) according to people such as Field basically: bring out acute pain in the carrageenin pattern among the 1513-1522.Get in 1 to the 2% carrageenin injection of solution big rat rear foot of 100 to 200 μ l.Injection back 3 to 4 hours, according to said method measure animal to heat and with the sensitivity of mechanical irritation.Before test or before the injection carrageenin, animal is thrown and test compound (0.01 to 50mg/kg).But the chemical compound per os or any non-through intestinal formula or topical administration to foot.The chemical compound of removing pain in this pattern can make the unusual pain of mechanicalness show on adding up with thermal hyperalgesia to reduce.
Chronic inflammation pain pattern
Adopt following a kind of method to bring out chronic inflammation pain:
1. be illustrated in (1999) Br.J.Pharmacol.128 (6) according to people such as Bertorelli basically: people such as the method for 1252-1258 and Stein are illustrated in (1998) Pharmacol.Biochem.Behav.31 (2): the method for 455-51, getting the complete Fu Luoyideshi adjuvant of 200 μ l (Complete Freund ' s Adjuvant) (the dead tulase (M.Tuberculosis) with drying of 0.1 milligram heat kill) is injected in the big rat rear foot: 100 μ l inject the instep, and 100 μ l inject plantar surface.
2. be illustrated in (1994) .J Neurosci.14 (10) according to people such as Abbadie basically: the method for 5865-5871, injection 150 μ lCFA (1.5mg) on the tibia midtarsal joints of big rat.
In its arbitrary method, before injection CFA, obtain the indivedual sensitivity bottom lines of each experimental animal rear foot earlier to machinery and thermostimulation.
Behind the injection CFA, according to unusual pain of thermal hyperalgesia, mechanicalness and the mechanical hyperalgesia of above-mentioned test big rat.Symptom for it is developed, test just behind injection CFA, begin to carry out big rat the 5th, 6 and 7 day the time.In the time of the 7th day, handle animal with test compound, morphine or base.Be that 1 to 5mg/kg morphine is as suitable positive controls with oral dose.The test compound dosage of typical case's employing is 0.01 to 50mg/kg.Chemical compound can be single bolus dispensing or before test, offer medicine every day 1,2 or 3 time before test, carry out a couple of days.But medicine per os or anyly non-ly give animal through intestinal formula approach or topical administration.
Its result may render a service percentage ratio (MPE) expression with the highest.The pain relieving that is defined as base of 0%MPE is renderd a service, and the animal that is defined as of 100%MPE recovers the preceding bottom line sensitivity of injection CFA.The resultant MPE of chemical compound that removes pain in this pattern is at least 30%.
The rational pain pattern of chronic neuropathic
The rational pain of chronic neuropathic system is illustrated in method among (1988) Pain 33:87-107 according to Bennett and Xie basically, adopts chronic contraction injury (CCI) processing big rat sciatic nerve and brings out.Anesthetized rat (for example: through the pentobarbital of intraperitoneal using dosage 50 to 65mg/kg and increase dosage according to need again).Scrape clean rear foot side and sterilization.Adopt aseptic technique, cut thigh in the rear foot side.Biceps femoris is cut into blunt end, exposes sciatic nerve.On wherein rear foot of every animal, according to the appointment between 1 to 2 millimeter every, with the lax ligation sciatic nerve of four ligatures.The sciatic nerve of another foot does not then have ligation and does not handle.Cover muscle subsequently, use wound clips or suture skin.The unusual pain of mechanicalness, mechanical hyperalgesia and thermal hyperalgesia according to above-mentioned analysis big rat.
When chemical compound in this pattern, before being about to test, be single bolus dispensing or before test, offer medicine every day 1,2 or 3 time, (0.01 to 50mg/kg to carry out a couple of days, per os, non-through intestinal formula or topical administration) time, this chemical compound can show the unusual pain of reduction mechanicalness, mechanical hyperalgesia and/or thermal hyperalgesia on statistics.
Claims (55)
- One kind as shown in the formula chemical compound or its pharmaceutically acceptable salt:
, wherein:(1) A is that N and B are CR 8Or (2) A is CR 5And B is N;Each is N or CR independently for Y and Z 1Each R 1Be hydrogen, halogen, cyano group, amino, C independently 1-C 4Alkyl, C 1-C 4Alkylhalide group, C 1-C 4Alkoxyl, C 1-C 4Halogen alkoxyl or list-or two-(C 1-C 4Alkyl) amino;R 2For: (i) hydrogen or halogen; Or(ii) C 1-C 6Alkyl, (C 3-C 7Cycloalkyl) C 0-C 4Alkyl, C 1-C 6Alkoxyl, C 1-C 6Aminoalkyl, C 1-C 6Hydroxy alkyl, C 2-C 6Alkyl ether, list-or two-(C 1-C 6Alkyl) amino C 0-C 4Alkyl or (4 to 7 element heterocycle alkyl) C 0-C 4Alkyl; Each replaces above group through 0 to 4 substituent group, and its substituent group is independently selected from halogen, cyano group, hydroxyl, amino, ketone group, list-or two-(C 1-C 6Alkyl) amino, C 1-C 6Alkyl C 1-C 6Alkoxyl or C 1-C 6Alkylhalide group.R 3Be hydrogen, COOH, C 1-C 4Alkyl, C 1-C 4Alkoxyl, C 1-C 4Alkoxy carbonyl or form the optional fused rings that is substituted together with R2;R 4Be hydrogen, halogen, cyano group, amino, COOH, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, C 1-C 4Alkoxyl, C 1-C 4Halogen alkoxyl or list-or two-(C 1-C 4Alkyl) amino;Each R 5Be hydrogen, halogen, cyano group, amino, COOH, C independently 1-C 4Alkyl, C 1-C 4Alkylhalide group, C 1-C 4Alkoxyl, C 1-C 4Halogen alkoxyl or list-or two-(C 1-C 4Alkyl) amino;R 8For:(i) hydrogen, hydroxyl, halogen, cyano group, amino, amino carbonyl or COOH; Or(ii) formula LR aGroup;Ar is 6 to 10 Yuans aryl or 5 to 10 Yuans heteroaryls, and its each 0 to 6 substituent group through independently being selected from following person replaces:(i) ketone group;(ii) formula LR aGroup; Or(iii) form the group through 0 to 35 to 7 Yuans annelated heterocycles that substituent group replaced together, its substituent group is independently selected from hydroxyl, halogen, amino, amino carbonyl, cyano group, nitro, ketone group, COOH, C 1-C 8Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkane anilide, C 1-C 8Alkane anilide oxygen base, C 1-C 8Alkoxy carbonyl, C 1-C 8Alkyl ether, C 1-C 8Hydroxy alkyl, C 1-C 8Alkylhalide group, phenyl C 0-C 8Alkyl, list or two (C 1-C 6Alkyl) amino C 0-C 4Alkyl, C 1-C 8Alkyl sulphur anilide or (4 to 7 element heterocycle) C 0-C 8Alkyl;L is independently selected from single covalent bond, O, (C=O), O (C=O), C (=O) O, OC (=O) O, S (O) at every turn when occurring m, N (R x), (C=O) N (R x), N (R x) (C=O), N (R x) S (O) m, S (O) mN (R x) or N[S (O) mR w] S (O) mWherein m is independently selected from 0,1 or 2 at every turn when occurring; R xWhen occurring, be independently selected from hydrogen, C at every turn 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 1-C 6Alkane anilide or C 1-C 6Alkyl sulphur anilide; And Rw is hydrogen or C 1-C 6Alkyl;R aWhen occurring, each independently is selected from every turn:(i) hydrogen, halogen, cyano group, nitro; Or(ii) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, (C 3-C 7Cycloalkyl) C 0-C 4Alkyl, C 1-C 8Alkylhalide group, C 2-C 8Alkyl ether, list-or two-(C 1-C 8Alkyl) amino or (3 to 10 element heterocycle) C 0-C 6Alkyl; Each 0 to 6 substituent group through independently being selected from following person of above group replaces:(a) hydroxyl, halogen, amino, amino carbonyl, cyano group, nitro, ketone group, COOH; And(b) C 1-C 8Alkyl, C 2-C 8Thiazolinyl, (C 3-C 7Cycloalkyl) C 0-C 4Alkyl, C 1-C 8Alkoxyl, C 1-C 8Alkylthio group, C 1-C 8Alkane anilide, C 1-C 8Alkane anilide oxygen base, C 1-C 8Alkoxy carbonyl, C 1-C 8Alkyl ether, C 1-C 8Hydroxy alkyl, C 1-C 8Alkylhalide group, phenyl C 0-C 8Alkyl, list-or two-(C 1-C 6Alkyl) amino carbonyl, list-or two-(C 1-C 6Alkyl) amino C 0-C 4Alkyl, C 1-C 8Alkyl sulphur anilide or (4 to 7 element heterocycle) C 0-C 8Alkyl, above group is respectively through independently being selected from hydroxyl, amino, C 1-C 4Alkyl or C 1-C 40 to 4 substituent group of alkoxyl replaces. - 2. chemical compound as claimed in claim 1 or salt, wherein Z is N.
- 3. chemical compound as claimed in claim 1 or 2 or salt, wherein Y is N.
- 4. chemical compound as claimed in claim 1 or 2 or salt, wherein Y is CH.
- 5. chemical compound as claimed in claim 1 or salt, wherein Y and Z are CH.
- 6. as described chemical compound of arbitrary claim or salt in the claim 1 to 5, wherein Ar is phenyl or 6 Yuans heteroaryls, and it respectively replaces through 0 to 3 substituent group, and its substituent group is independently selected from (a) formula LR aGroup or (b) form optional 5 to 7 Yuans condensed carbocyclic rings or heterocycles that are substituted together.
- 7. chemical compound as claimed in claim 6 or salt, wherein Ar is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl or pyridazinyl, its each 0,1 or 2 substituent group through independently being selected from following person replaces: halogen, cyano group, C 1-C 6Alkyl, C 1-C 6Alkylhalide group, C 1-C 6Hydroxy alkyl, C 1-C 6Cyano group alkyl, C 1-C 6Alkoxyl, C 1-C 6Halogen alkoxyl, C 1-C 6Alkyl ether, C 1-C 6Alkane anilide, C 1-C 6Alkyl sulphur anilide, C 1-C 6Alkylhalide group sulphur anilide, amino, list-or two-(C 1-C 6Alkyl) amino or 5-or 6-element heterocycle alkyl.
- 8. chemical compound as claimed in claim 7 or salt, wherein Ar is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl or pyridazinyl, its each 0,1 or 2 substituent group through independently being selected from following person replaces: halogen, cyano group, amino, C 1-C 4Alkyl, C 1-C 4Hydroxy alkyl, C 1-C 4Cyano group alkyl, C 1-C 6Alkoxyl, C 1-C 4Alkane anilide, C 1-C 4Alkylhalide group, C 1-C 4Alkyl sulphur anilide, C 1-C 4Alkylhalide group sulphur anilide, list-or two-(C 1-C 4Alkyl) amino or 5-or 6-element heterocycle alkyl.
- 9. as the described chemical compound of arbitrary claim or salt, wherein R in the claim 1 to 8 4Be halogen, cyano group, C 1-C 6Alkyl, C 1-C 6Alkylhalide group, C 1-C 6Alkoxyl or C 1-C 6The halogen alkoxyl.
- 10. chemical compound as claimed in claim 9 or salt, wherein R 4Be halogen, cyano group, methyl or trifluoromethyl.
- 11. as described chemical compound of arbitrary claim or salt in the claim 1 to 10, wherein:B is CR 8AndR 8Be(i) hydrogen, hydroxyl, cyano group, amino carbonyl or COOH; Or(ii) C 1-C 8Alkoxyl, C 1-C 8Alkylhalide group, C 1-C 8Alkane anilide, list-or two-(C 1-C 8Alkyl) amino, 4 to 7 element heterocycle alkyl or (4 to 7 element heterocycle alkyl) amino, each 0 to 2 substituent group through independently being selected from following person of above group replaces:(a) hydroxyl, halogen, cyano group, amino, amino carbonyl, or COOH; Or(b) C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 1-C 6Alkylhalide group, (C 3-C 7Cycloalkyl) C 0-C 4Alkyl, C 1-C 6Alkoxyl, C 1-C 6Alkoxy carbonyl, C 2-C 6Alkyl ether, list-or two-(C 1-C 6Alkyl) amino C 0-C 4Alkyl, list-or two-(C 1-C 6Alkyl) amino carbonyl, or (4 to 7 element heterocycle) C 0-C 4Alkyl, above group is respectively through independently being selected from hydroxyl, amino, C 1-C 4Alkyl or C 1-C 40 to 2 substituent group of alkoxyl replaces.
- 12. chemical compound as claimed in claim 11 or salt, wherein R 8Be single-or two-(C 1-C 8Alkyl) amino, piperazinyl, piperidyl or pyrrolidinyl, above group is by being unsubstituted or a substituent group through independently being selected from following person is replaced: hydroxyl, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 1-C 4Alkylhalide group, C 1-C 6Alkoxyl, (single-or two-(C 1-C 6Alkyl) C amino) 0-C 2Alkyl or (4-to 7-element heterocycle alkyl) C 0-C 2Alkyl, its each multiple randomly through hydroxyl, C 1-C 4Alkyl or C 1-C 4Alkoxyl replaces.
- 13. as described chemical compound of arbitrary claim or salt in the claim 1 to 12, it has following formula:
- 14. chemical compound as claimed in claim 13 or salt, it has following formula:
- 15. chemical compound as claimed in claim 14 or salt, wherein:Y and Z are N or CH independently;R 2Be hydrogen, halogen, C 1-C 4Alkyl or C 2-C 4Alkyl ether;R 3Be hydrogen;R 4Be halogen, cyano group, C 1-C 6Alkyl, C 1-C 6Alkylhalide group, C 1-C 6Alkoxyl or C 1-C 6The halogen alkoxyl;R 8Be hydrogen, list-or two-(C 1-C 8Alkyl) amino, piperazinyl, piperidyl or pyrrolidinyl, above group is by being unsubstituted or a substituent group through independently being selected from following person is replaced: hydroxyl, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 1-C 4Alkylhalide group, C 1-C 6Alkoxyl, (single-or two-(C 1-C 6Alkyl) C amino) 0-C 2Alkyl or (4-to 7-element heterocycle alkyl) C 0-C 2Alkyl, its each multiple randomly through hydroxyl, C 1-C 4Alkyl or C 1-C 4Alkoxyl replaces; AndAr is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl or pyridazinyl, and each 0,1 or 2 substituent group through independently being selected from following person of above group replaces: halogen, cyano group, amino, C 1-C 4Alkyl, C 1-C 4Hydroxy alkyl, C 1-C 4Cyano group alkyl, C 1-C 6Alkoxyl, C 1-C 4Alkane anilide, C 1-C 4Alkylhalide group, C 1-C 4Alkyl sulphur anilide, C 1-C 4Alkylhalide group sulphur anilide, list-or two-(C 1-C 4Alkyl) amino or 5-or 6-element heterocycle alkyl.
- 16. chemical compound as claimed in claim 15 or salt, wherein this chemical compound has following formula:
Wherein:R 4Be cyano group, C 1-C 4Alkyl or C 1-C 4Alkylhalide group;R 8Be singly-or two-(C 1-C 8Alkyl) amino, piperazinyl, piperidyl or pyrrolidinyl, above group is by being unsubstituted or a substituent group through independently being selected from following person is replaced: hydroxyl, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 1-C 4Alkylhalide group, C 1-C 6Alkoxyl, (single-or two-(C 1-C 6Alkyl) C amino) 0-C 22Alkyl or (4-to 7-element heterocycle alkyl) C 0-C 2Alkyl, its each multiple randomly through hydroxyl, C 1-C 4Alkyl or C 1-C 4Alkoxyl replaces; AndAr is that its substituent group is independently selected from through 1 or 2 pyridine radicals that substituent group replaced: halogen, cyano group, C 1-C 4Alkyl, C 1-C 4Alkylhalide group, C 1-C 4Alkyl sulphur anilide, C 1-C 4Alkylhalide group sulphur anilide, list-or two-(C 1-C 4Alkyl) amino. - 17. as described chemical compound of arbitrary claim or salt in the claim 1 to 12, wherein this chemical compound has following formula:
- 18. chemical compound as claimed in claim 17 or salt, wherein:Y and Z are N or CH independently;R 2Be hydrogen, halogen, C 1-C 4Alkyl or C 2-C 4Alkyl ether;R 3Be hydrogen;R 4Be halogen, cyano group, C 1-C 6Alkyl, C 1-C 6Alkylhalide group, C 1-C 6Alkoxyl or C 1-C 6The halogen alkoxyl;Each R 5Be hydrogen, halogen, cyano group, COOH, C independently 1-C 6Alkyl, C 1-C 6Alkylhalide group, C 1-C 6Alkoxyl, or C 1-C 6The halogen alkoxyl; AndAr is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl or pyridazinyl, and each 0,1 or 2 substituent group through independently being selected from following person of above group replaces: halogen, cyano group, amino, C 1-C 4Alkyl, C 1-C 4Hydroxy alkyl, C 1-C 4Cyano group alkyl, C 1-C 6Alkoxyl, C 1-C 4Alkane anilide, C 1-C 4Alkylhalide group, C 1-C 4Alkyl sulphur anilide, C 1-C 4Alkylhalide group sulphur anilide, list-or two-(C 1-C 4Alkyl) amino or 5-or 6-element heterocycle alkyl.
- 19. as described chemical compound of arbitrary claim or salt in the claim 1 to 18, wherein this chemical compound is the VR1 antagonist and moves IC in the analytical test at capsaicin receptor calcium 50Value is 1 little not ear or following.
- 20. chemical compound as claimed in claim 19 or salt, wherein this chemical compound urges in the analyzed in vitro test of effect at capsaicin receptor, equals IC in compound concentrations 50During value, do not show the agonist activity that to detect.
- 21. a medical component, it comprises the combination as the described at least a chemical compound of claim 1 to 20 and physiologically acceptable supporting agent or excipient.
- 22. medical component as claimed in claim 21, wherein this constituent is through being allocated as injection liquid, aerosol, cream, gel, pill, capsule, syrup or transdermal patch.
- 23. the method for a calcium conduction that reduces the cell capsaicin receptor, this method comprise and make the cell of expressing capsaicin receptor and contact as the described chemical compound of arbitrary claim in the claim 1 to 20, the calcium of using the reduction capsaicin receptor conducts.
- 24. method as claimed in claim 23, wherein this cell is in vivo to contact in animal body.
- 25. method as claimed in claim 24, wherein this cell is a neuronal cell.
- 26. method as claimed in claim 25, wherein this cell is a urothelial cell.
- 27. method as claimed in claim 24, this chemical compound was to be present within the body fluid of animal when wherein contact was carried out.
- 28. method as claimed in claim 24, wherein this animal is human.
- 29. method as claimed in claim 24, wherein this chemical compound or salt are oral administrations.
- 30. one kind in vitro inhibition cephrol part and the bonded method of capsaicin receptor, this method comprise with capsaicin receptor with contact as described chemical compound of arbitrary claim or salt in the claim 1 to 20, used amount is to be enough to suppress the cephrol part combine with capsaicin receptor with detecting.
- 31. one kind is suppressed cephrol part and the bonded method of capsaicin receptor in patient's body, this method comprises the cell of will express capsaicin receptor and contacts as described chemical compound of arbitrary claim or salt in the claim 1 to 20, used amount is to be enough to combine with the capsaicin receptor of expressing through the clone at the external cephrol part that suppresses with detecting, and thereby in patient's body the combining of inhibition cephrol part and capsaicin receptor.
- 32. method as claimed in claim 31, wherein this patient is human.
- 33. method as claimed in claim 31, wherein the compound concentrations that exists in patient's blood is 1 micromole or following.
- 34. the method for a symptom that the capsaicin receptor regulating action is responded at patient's disposition, this method comprises with the treatment effective dose patient dispensing as described chemical compound of arbitrary claim or salt in the claim 1 to 20, and thereby these symptoms of reduction of patient.
- 35. method as claimed in claim 34, patient wherein suffer from (i) be exposed to capsaicin, (ii) be exposed to that heat caused burn burning of stimulating, (iii) be exposed to light and caused or stimulate, (iv) be exposed to that tear gas, infectiousness agent, air pollutants or pepper spray are causedly burnt, bronchoconstriction or stimulation, or (v) be exposed to and sour causedly burn or stimulate.
- 36. method as claimed in claim 34, wherein this symptom is asthma or chronic obstructive pulmonary disease.
- 37. a method of disposing patient's pain, it comprises with the treatment effective dose patient dispensing as described chemical compound of arbitrary claim or salt in the claim 1 to 20, and thereby the pain of reduction of patient.
- 38. method as claimed in claim 37, wherein the concentration of chemical compound that exists in patient's blood or salt is 1 little More or following.
- 39. method as claimed in claim 37, wherein this patient is for suffering from neuropathic pain.
- 40. method as claimed in claim 37, wherein this pain is relevant with the symptom that is selected from following person: the postoperative pain syndrome of mastectomy, deformed limb pain, phantom limb pain, the oral cavity neuropathic pain, toothache, postherpetic neuralgia, diabetic neuropathy, the reflection sympathetic nerve loses supports disease, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgia, Ji Lan-Bai Rui syndrome, Bernhards disease, syndrome is burnt in the oral cavity, two side periphery neuropathy, causalgia, the neuritis, neuronitis, neuralgia, the neuropathy that AIDS is relevant, the neuropathy that MS is relevant, the pain that spinal cord injury is relevant, the pain that operation is relevant, musculoskeletal pain, backache, headache, migraine, angor, childbirth, hemorrhoid, dyspepsia, Sha Erkeshi pain, intestinal tympanites, menstruation, cancer, be exposed to venom, intestinal swashs hot-tempered disease, inflammatory intestinal portion's disease or wound.
- 41. method as claimed in claim 37, patient wherein is human.
- 42. dispose the method that the patient scratches where it itches for one kind, it comprises with the treatment effective dose patient dispensing as described chemical compound of arbitrary claim or salt in the claim 1 to 20, and thereby the scratching where it itches of reduction of patient.
- 43. a method of disposing patient cough or singultus, it comprises with the treatment effective dose patient's dispensing as described chemical compound of arbitrary claim or salt in the claim 1 to 20, and thereby the cough or the singultus of reduction of patient.
- 44. a method of disposing patient's urinary incontinence or overactive bladder, it comprises with the treatment effective dose patient dispensing as described chemical compound of arbitrary claim or salt in the claim 1 to 20, and thereby the urinary incontinence or the overactive bladder of reduction of patient.
- 45. a method that promotes that the obese patient loses weight, it comprises with the treatment effective dose offers medicine as described chemical compound of arbitrary claim or salt in the claim 1 to 20 to the patient, and thereby promotes that weight in patients alleviates.
- 46. as described chemical compound of arbitrary claim or salt in the claim 1 to 20, wherein this chemical compound is through radio-labeled.
- 47. the method for evaluation and the bonded medicament of capsaicin receptor, it comprises:(a) make capsaicin receptor with as claimed in claim 46 allowing under the bonded condition of VR1 regulator and capsaicin receptor through radiolabeled chemical compound contact, thereby produce through bonded and through the VR1 of labelling regulator;(b) do not have the situation detection signal of test medicine, this signal be with through combining and corresponding through the amount of the VR1 of labelling regulator;(c) will contact with test medicine through combination and through the VR1 of labelling regulator;(d) at the situation detection signal that has test medicine to exist, this signal be with through combining and corresponding through the amount of the VR1 of labelling regulator; And(e) detecting measured signal in step (d) and in step (b) is compared the reduction of signal, and thereby judgement and the bonded medicament of capsaicin receptor.
- 48. one kind is determined at the method that whether has capsaicin receptor to exist in the sample, this method comprises the following steps:(a) sample is being contacted with allowing under the bonded condition of chemical compound and capsaicin receptor as the described chemical compound of arbitrary claim in the claim 1 to 20; And(b) detecting and the bonded compound concentrations of capsaicin receptor, and be determined at therefore whether the capsaicin receptor existence is arranged in the sample.
- 49. method as claimed in claim 48, wherein this chemical compound is through radio-labeled, and the step of wherein detecting comprises the following steps:(i) with the chemical compound of not combination and through bonded compound separation; And(ii) detect in sample, whether to have and exist through bonded chemical compound.
- 50. the pharmaceutical preparation of a packing, it comprises:(a) in container, comprise medical composition as claimed in claim 21; And(b) use the description of said composition with management of pain.
- 51. the pharmaceutical preparation of a packing, it comprises:(a) in container, comprise medical composition as claimed in claim 21; And(b) use said composition to dispose the description of cough or singultus.
- 52. the pharmaceutical preparation of a packing, it comprises:(a) in container, comprise medical composition as claimed in claim 21; And(b) use said composition to dispose fat description.
- 53. the pharmaceutical preparation of a packing, it comprises:(a) in container, comprise medical composition as claimed in claim 21; And(b) use said composition to dispose the description of urinary incontinence or overactive bladder.
- 54. as the purposes of described chemical compound of arbitrary claim or salt in the claim 1 to 20, it is in order to make the used medicine of symptom that the capsaicin receptor regulating action is responded for disposing.
- 55. purposes as claimed in claim 54, wherein, this symptom is pain, asthma, chronic obstructive pulmonary disease, cough, singultus, obesity, urinary incontinence, overactive bladder, be exposed to capsaicin, because of burning of being exposed to that heat causes or stimulate, because of burning of being exposed to that light causes or stimulate, because of burning of being exposed to that tear gas, air pollutants or pepper spray cause, bronchoconstriction or stimulation, or because of burning of being exposed to that acid causes or stimulate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64719005P | 2005-01-25 | 2005-01-25 | |
| US60/647,190 | 2005-01-25 |
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| CN101232885A true CN101232885A (en) | 2008-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2006800031817A Pending CN101232885A (en) | 2005-01-25 | 2006-01-25 | Substituted pyridazinyl- and pyrimidinyl-quinolin-4-ylamine analogues |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20080175794A1 (en) |
| EP (1) | EP1841430A4 (en) |
| JP (1) | JP2008528613A (en) |
| CN (1) | CN101232885A (en) |
| AU (1) | AU2006208042A1 (en) |
| CA (1) | CA2594998A1 (en) |
| WO (1) | WO2006081388A2 (en) |
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| CN113939295A (en) * | 2019-03-20 | 2022-01-14 | 金翅雀生物公司 | Pyridazinones and methods of use thereof |
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| DE10323345A1 (en) | 2003-05-23 | 2004-12-16 | Zentaris Gmbh | New pyridopyrazines and their use as kinase inhibitors |
| TW200510373A (en) * | 2003-07-14 | 2005-03-16 | Neurogen Corp | Substituted quinolin-4-ylamine analogues |
| TW200621251A (en) * | 2004-10-12 | 2006-07-01 | Neurogen Corp | Substituted biaryl quinolin-4-ylamine analogues |
| PE20080145A1 (en) | 2006-03-21 | 2008-02-11 | Janssen Pharmaceutica Nv | TETRAHYDRO-PYRIMIDOAZEPINE AS MODULATORS OF TRPV1 |
| PE20091102A1 (en) | 2007-12-17 | 2009-07-25 | Janssen Pharmaceutica Nv | IMIDAZOLO-, OXAZOLO-, AND THIAZOLOPYRIMIDINE MODULATORS OF TRPV1 |
| WO2009132050A2 (en) | 2008-04-21 | 2009-10-29 | Otonomy, Inc. | Auris formulations for treating otic diseases and conditions |
| CA2731769C (en) | 2008-07-21 | 2013-09-10 | Otonomy, Inc. | Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders |
| EP2179992A1 (en) | 2008-10-21 | 2010-04-28 | Bayer Schering Pharma Aktiengesellschaft | Sulfon substituted aniline pyrimidine derivatives as CDK inhibitors, their manufacture and use as medicine |
| EP2179993A1 (en) | 2008-10-21 | 2010-04-28 | Bayer Schering Pharma Aktiengesellschaft | Sulfoxide substituted aniline pyrimidine derivatives as CDK inhibitors, their manufacture and use as medicine |
| US9133123B2 (en) | 2010-04-23 | 2015-09-15 | Cytokinetics, Inc. | Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use |
| AR081626A1 (en) * | 2010-04-23 | 2012-10-10 | Cytokinetics Inc | AMINO-PYRIDAZINIC COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE OF THE SAME TO TREAT CARDIAC AND SKELETIC MUSCULAR DISORDERS |
| AR081331A1 (en) | 2010-04-23 | 2012-08-08 | Cytokinetics Inc | AMINO- PYRIMIDINES COMPOSITIONS OF THE SAME AND METHODS FOR THE USE OF THE SAME |
| AU2012326246B2 (en) * | 2011-10-18 | 2015-09-17 | Fmc Corporation | Stable formulations containing fumed aluminum oxide |
| GB2566622B (en) * | 2014-05-08 | 2019-07-10 | Tosoh F Tech Inc | 5-(Trifluoromethyl)pyrimidine derivatives and method for producing same |
| WO2018005830A1 (en) | 2016-06-29 | 2018-01-04 | Otonomy, Inc. | Triglyceride otic formulations and uses thereof |
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| TW200406390A (en) * | 2002-01-17 | 2004-05-01 | Neurogen Corp | Substituted quinazolin-4-ylamine analogues |
| JP2006515846A (en) * | 2002-12-13 | 2006-06-08 | ニューロジェン・コーポレーション | 2-Substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators |
| WO2005023807A2 (en) * | 2003-09-09 | 2005-03-17 | Neurogen Corporation | 4 - heterobicyclyamino - substituted quinazolines and analogues therof as capsaicin - antagonists |
| TW200621251A (en) * | 2004-10-12 | 2006-07-01 | Neurogen Corp | Substituted biaryl quinolin-4-ylamine analogues |
-
2006
- 2006-01-25 CA CA002594998A patent/CA2594998A1/en not_active Abandoned
- 2006-01-25 EP EP06719649A patent/EP1841430A4/en not_active Withdrawn
- 2006-01-25 AU AU2006208042A patent/AU2006208042A1/en not_active Abandoned
- 2006-01-25 CN CNA2006800031817A patent/CN101232885A/en active Pending
- 2006-01-25 WO PCT/US2006/002871 patent/WO2006081388A2/en active Application Filing
- 2006-01-25 JP JP2007553251A patent/JP2008528613A/en active Pending
- 2006-01-25 US US11/883,005 patent/US20080175794A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113939295A (en) * | 2019-03-20 | 2022-01-14 | 金翅雀生物公司 | Pyridazinones and methods of use thereof |
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| Publication number | Publication date |
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| AU2006208042A1 (en) | 2006-08-03 |
| JP2008528613A (en) | 2008-07-31 |
| US20080175794A1 (en) | 2008-07-24 |
| CA2594998A1 (en) | 2006-08-03 |
| EP1841430A4 (en) | 2009-07-29 |
| WO2006081388A2 (en) | 2006-08-03 |
| EP1841430A2 (en) | 2007-10-10 |
| WO2006081388A3 (en) | 2007-08-23 |
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